ANTIBIOTICS
When antibiotics were first discovered they were called “wonder drugs”
Antibiotic is a drug that fights bacter...
““AntibioticsAntibiotics are defined as chemical substances or compoundsare defined as chemical substances or compounds
pr...
Requirements for a substance to be considered as an antibioticRequirements for a substance to be considered as an antibiot...
 HHistory of antibiotics can be described inistory of antibiotics can be described in two segmentstwo segments early hist...
TREATMENT OF INFECTIOUS DISEASES PRIOR TO ANTIBIOTICS.
Centuries earlier, humans had learned to use crude preparations for...
Modern HistoryModern History Late 1800’s = Search for antibiotics began with the growing acceptance of the germ theory of...
 CLASSIFICATIONCLASSIFICATION :: Antibiotics are classified in many ways based on chemical structure, source,itsAntibioti...
 Antibiotic activityAntibiotic activity :Based on their activity against different m.o’s they are divided in to:Based on ...
Beta-lactam antibiotics will be examined in fourBeta-lactam antibiotics will be examined in four
groups, includinggroups,...
 Penicillin was discovered inPenicillin was discovered in 19281928 byby Alexander FlemingAlexander Fleming, who, who
noti...
Penicillium mould
(penicillium notatum)
Historical background of penicillinsHistorical background of penicillins
 Alexander Fleming was born in Loudon, Scotland ...
 It was aIt was a Serendipitous observation(fortuitous accident)Serendipitous observation(fortuitous accident) i.e (happe...
 This newly discovered active substance(penicillin) was effectiveThis newly discovered active substance(penicillin) was e...
Commercial production of antibioticsCommercial production of antibiotics
The general scheme may be divided into six stepsT...
 Once the penicillin is released from the fungal cells, the compoundOnce the penicillin is released from the fungal cells...
Biological sources of penicillinBiological sources of penicillin
 The first naturally occurring benzyl penicillin (penici...
5 Classes of Penicillins
Natural Penicillins (Fermentation derived penicillins)
Penicillin G ,Penicillin V
Semi synthetic ...
R =
STRUCTURE
OF PENICILLINS
Penicillin G (Benzylpenicillin)Penicillin G (Benzylpenicillin)
 Penicillin G is also referred to asPenicillin G is also r...
N
S
COOH
H
CH3
CH3
HH
O
HNCH2C
O
O
It withdraws the electrons away
from the corbonyl oxygen and
reduce the tendency to act...
N
S
COOH
H
CH3
CH3
HH
O
HNCH2C
O
OCH3
OCH3
Strategy is putting
two ortho- methoxy
groups on the aromatic
ring.
Bulky group...
Isoxazoyl Penicillins
Penicillinase- resistant penicillins or β- lactamase- resistant penicillins
R1 R2
Oxacillin H H
Clox...
 To sum up acid resistant penicillins would be the drugs of first choice against an infection.
 If the bacteria proved r...
The acidic stability of the ampicillin also attributes the electron withdrawing character of the primary
amino group which...
Amoxicillin (Amoxil) (p-hydroxy Ampicillin)
Amoxicillin is the very similar in structure like ampicillin, the only differe...
Ampicillin synthesis:
Directly acylating 6-APA with phenylglycine chloride hydrochloride
Ampicillin
Amoxicillin synthesis:...
Nomenclature of PenicillinsNomenclature of Penicillins
Nomenclature of penicillins was done in different systemsNomenclatu...
As derivatives of Penam:
Unsubstituted bicyclic system together with amide
corbonyl group has been named as penam.
Accordi...
Stereo chemistryStereo chemistry The penicillin molecule contains three chiral carbon atoms at C-3, C-5 andThe penicillin...
Reactions: Hydrolysis of penicillins by hot and cold dilute mineral acidReactions: Hydrolysis of penicillins by hot and co...
There are also a variety of acylases that have been isolated from some bacteria, and
these enzymes cleave the acylamino si...
N
S
COO
H
CH3
CH3
HH
O
HNCR
O
Thiazolidine
ring
β-Lactam
ring
Cis orientation of hydrogens
(stereochemistry) are essential...
Key features of structure
 1. β-lactam ring
 a. "Lactam" is a word for any cyclic amide (the word "lactone" is used for
...
Penicillins are….
a group of antibiotics that contain 6-amino penicillanic acid side chain attached
to the 6-amino group.
...
 SAR of “R” group:SAR of “R” group:
 C-6 amino west end substitution:C-6 amino west end substitution:
The design and dev...
 Broad spectrum activity is associated with the presence ofBroad spectrum activity is associated with the presence of αα-...
Plasma membrane
Peptidoglycan cell wall
(rigid coating around the membrane)
Lipopolysaccharide layer
(LPS)
Gram +ve Gram –...
Beta-lactam antibiotics are relativelyBeta-lactam antibiotics are relatively
non-toxic to humans why?non-toxic to humans w...
Mechanism of action of penicillinsMechanism of action of penicillins
 The primary mechanism of the action of beta-lactam ...
 Transpeptidase connects the little peptide chains perpendicular to the NAM chains.Transpeptidase connects the little pep...
(Peptidoglycan cell wall)
N-acetylglucosamine
N-acetylmuramic acid
Transpeptidase located
within the cell membrane
are res...
Cross-linking of bacterial cell walls inhibited by penicillin
 Sugars contained in the cell wall structure of bacteria.Sugars contained in the cell wall structure of bacteria.
 N-ace...
Mechanisms of transpeptidase crosslinking and penicillin inhibition.
 Microbial resistance toMicrobial resistance to ββ-lactam antibiotics-lactam antibiotics like penicillins, cephalosporins...
The agents Clavalunic acid, sulbactam and tazobactam have also been developed as
β-lactamase inhibitors.
Sulbactum + ampic...
 Clavulanic acid:Clavulanic acid:
clavalunic acid was isolated from streptomyces clavuligerus by Bechams inclavalunic aci...
Resistance to the B-lactam Antibiotics
1. Differences in PBP’s
- Decreased affinity of the PBP for the binding of the Abx
...
 Penicillin’s may be used to treat infections such as urinary tract infections.Penicillin’s may be used to treat infectio...
 Penicillins are available only with a prescription. Penicillin’s are useful againstPenicillins are available only with a...
 Adverse/toxic effects of penicillins:-
 Although most penicillins are safe for the majority of people, some people may
...
After 7 days this allergy occurred her after penicillin has been
taken for throat Infection. That is Late hypersensityvity.
Nausea Dizziness Headache
In((inflammation
of blood vessels)
Skinrashes fever Bronchospasm
(Constriction of the
Airways of...
Less common side effects of penicillins are
 1. Nausea 2. Diziness 3. Head ache 4. skin rashes 5. Bronchospasm 6. vasculi...
Hypersensitivity or allergic reactions :
 Hypersensitivity to penicillin’s is caused by the degradation
products of penic...
 A)A) Immediate hypersensitivityImmediate hypersensitivity:: -- This occursThis occurs within 20 minwithin 20 min. of par...
Penicillin's advantages and disadvantagesPenicillin's advantages and disadvantages
 Penicillin's disadvantagesPenicillin'...
Key pointsKey points
 Penicillins have aPenicillins have a bicyclic structurebicyclic structure consisting of aconsisting...
Prof. Panchumarthy Ravisankar
penicillins - power point - History,mechanism of action,classification,chemistry, SAR, Nomenclature, uses, sideeffects-Med...
penicillins - power point - History,mechanism of action,classification,chemistry, SAR, Nomenclature, uses, sideeffects-Med...
penicillins - power point - History,mechanism of action,classification,chemistry, SAR, Nomenclature, uses, sideeffects-Med...
penicillins - power point - History,mechanism of action,classification,chemistry, SAR, Nomenclature, uses, sideeffects-Med...
penicillins - power point - History,mechanism of action,classification,chemistry, SAR, Nomenclature, uses, sideeffects-Med...
penicillins - power point - History,mechanism of action,classification,chemistry, SAR, Nomenclature, uses, sideeffects-Med...
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Antibiotics - Penicillin's - power point - History, mechanism of action, classification, chemistry, SAR, Nomenclature, uses, side effects- Medicinal chemistry.

Dr. P. Ravisankar M. Pharm., Ph.D.
HOD .,
Vignan Pharmacy college
vadlamudi- Guntur-A.P, India.
banuman35@gmail.com
Phone: 0 9059994000
0 9000199106

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penicillins - power point - History,mechanism of action,classification,chemistry, SAR, Nomenclature, uses, sideeffects-Medicinal chemistry

  1. 1. ANTIBIOTICS When antibiotics were first discovered they were called “wonder drugs” Antibiotic is a drug that fights bacterial infection Dr. PANCHUMARTHY RAVI SANKAR M. Pharm, Ph.D. Professor & HOD Vignan pharmacy college, Vadlamudi- Guntur, A.P, India.
  2. 2. ““AntibioticsAntibiotics are defined as chemical substances or compoundsare defined as chemical substances or compounds produced by various species of microorganisms such as bacteriaproduced by various species of microorganisms such as bacteria and fungi, which in low concentrations destroy, kill or inhibit theand fungi, which in low concentrations destroy, kill or inhibit the growth of other species of microorganisms.”growth of other species of microorganisms.” Greek wordsGreek words anti = against ; bios = lifeanti = against ; bios = life Vuillemin to define antibiotics literally meaning “against life”Vuillemin to define antibiotics literally meaning “against life” In 1942 Waksman proposed the widely cited definition that “an antibiotic is aIn 1942 Waksman proposed the widely cited definition that “an antibiotic is a substance produced by microorganisms, which has the capacity of inhibiting the growthsubstance produced by microorganisms, which has the capacity of inhibiting the growth and even of destroying other microorganisms”.and even of destroying other microorganisms”.  The word antibiotic came from the wordThe word antibiotic came from the word antibiosisantibiosis a terma term coined incoined in 18891889 by Louis Pasteur'sby Louis Pasteur's pupilpupil Paul VuilleminPaul Vuillemin whichwhich means a process by whichmeans a process by which life could be used to destroy lifelife could be used to destroy life.. However, by acylating it with various acid derivatives, more thanHowever, by acylating it with various acid derivatives, more than 50,00050,000 semisynthetic penicillins have been made, of whichsemisynthetic penicillins have been made, of which less than 30less than 30 are currently used in medicine.are currently used in medicine. DEFINITION :
  3. 3. Requirements for a substance to be considered as an antibioticRequirements for a substance to be considered as an antibiotic  -It should have a-It should have a wide spectrumwide spectrum of activity with theof activity with the ability to destroyability to destroy or inhibitor inhibit many different species of pathogenic organisms.many different species of pathogenic organisms.  -It should be-It should be eliminated completelyeliminated completely from the body.from the body.  -It should-It should not produce adverse and side effectsnot produce adverse and side effects..  -It should-It should antagonizes the growthantagonizes the growth or survival of one or more speciesor survival of one or more species of micro- organisms.of micro- organisms.  -It should be-It should be highly effectivehighly effective in low concentrations.in low concentrations.  -It should be-It should be nonallergenicnonallergenic to the host.to the host.  -It should-It should notnot eliminate theeliminate the normal floranormal flora of the host.of the host.  -It should be-It should be able to reachable to reach the part of the human body wherethe part of the human body where the infection is occurring.the infection is occurring.  -It should be-It should be inexpensiveinexpensive andand easy to produceeasy to produce..  -It should be-It should be chemically-stablechemically-stable (have a long shelf-life).(have a long shelf-life).  -It is a product of metabolism (although it may be duplicated or even-It is a product of metabolism (although it may be duplicated or even have been anticipated by chemical synthesis).have been anticipated by chemical synthesis).
  4. 4.  HHistory of antibiotics can be described inistory of antibiotics can be described in two segmentstwo segments early history and modernearly history and modern historyhistory..  Most important is the discovery of penicillin by SIRMost important is the discovery of penicillin by SIR Alexander Fleming.Alexander Fleming.  EARLY HISTORYEARLY HISTORY::  During ancient timesDuring ancient times ::  Long ago before 20Long ago before 20thth century there was no proper treatment for diseases.century there was no proper treatment for diseases. The diseases caused byThe diseases caused by Mycobacterium tuberculosis, Mycobacterium lepraeMycobacterium tuberculosis, Mycobacterium leprae were not identifiedwere not identified ..  Over 2,500Over 2,500 years ago , Chinese usedyears ago , Chinese used plants and moldy cheese usedplants and moldy cheese used to treat infected wounds.to treat infected wounds.  As early as 500 to 600 BC, molded curd of soybean was used in Chinese folk medicine to treatAs early as 500 to 600 BC, molded curd of soybean was used in Chinese folk medicine to treat boils and carbuncles.boils and carbuncles.  The ancientThe ancient Egyptians used honey + lint (softEgyptians used honey + lint (soft cotton cloth covering and protecting wounds)+cotton cloth covering and protecting wounds)+lardlard (melted fat of pigs) used as ointment(melted fat of pigs) used as ointment for dressing wounds.for dressing wounds.  EgyptiansEgyptians have often been foundhave often been found onions in body cavities of mummiesonions in body cavities of mummies. They used onions,. They used onions, garlic and radish herb therapeutically. Infact they havegarlic and radish herb therapeutically. Infact they have anti-infective properties.anti-infective properties.  GreeksGreeks and Indians usedand Indians used mouldsmoulds and other plants to treat infections.and other plants to treat infections.  InIn Greece and Serbia, moldy breadGreece and Serbia, moldy bread was traditionally used to treat wounds andwas traditionally used to treat wounds and infections.infections.  Warm soilWarm soil was used bywas used by RussiansRussians to cure infected wounds.to cure infected wounds.  Sumerian doctorsSumerian doctors gave patientsgave patients beer soup mixed with turtle shells and snakebeer soup mixed with turtle shells and snake skinsskins..  Babylonian doctorsBabylonian doctors healed the eyes using a mixture ofhealed the eyes using a mixture of frog bile and sour milkfrog bile and sour milk .. Sri Lankan armySri Lankan army usedused oil cake (sweetmeat)oil cake (sweetmeat) to serve as antibacterial.to serve as antibacterial.
  5. 5. TREATMENT OF INFECTIOUS DISEASES PRIOR TO ANTIBIOTICS. Centuries earlier, humans had learned to use crude preparations for the topical treatment of infections.
  6. 6. Modern HistoryModern History Late 1800’s = Search for antibiotics began with the growing acceptance of the germ theory ofLate 1800’s = Search for antibiotics began with the growing acceptance of the germ theory of disease(disease(Louis Pasteur was one of the first recognized physicians who observed that bacteria could beLouis Pasteur was one of the first recognized physicians who observed that bacteria could be used to kill other bacteria)used to kill other bacteria)  1871 = The surgeon joseph lister found urine contaminated with1871 = The surgeon joseph lister found urine contaminated with mould couldn't kill the bacteria.mould couldn't kill the bacteria.  1890’s = German doctors Rudolf emmerich, oscar low made1890’s = German doctors Rudolf emmerich, oscar low made pyocyansepyocyanse from microbes. It was the first antibiotic usedfrom microbes. It was the first antibiotic used in hospitals but the drug did not work.in hospitals but the drug did not work.  1909 =First modern chemotherapeutic agent1909 =First modern chemotherapeutic agent SALVARSANSALVARSAN for thefor the treatment of syphilis.(Paul Ehrlich)treatment of syphilis.(Paul Ehrlich)  19281928 = Scottish bacteriologist= Scottish bacteriologist Sir Alexander Fleming discovered enzymeSir Alexander Fleming discovered enzyme lysozyme and the antibiotic substance penicillin.lysozyme and the antibiotic substance penicillin.  1932 = Gerhard Domagk discovered1932 = Gerhard Domagk discovered ProntosilProntosil a prodrug.a prodrug.  1936 = Sulfanilamide the first synthetic sulfonamide in human medicine.1936 = Sulfanilamide the first synthetic sulfonamide in human medicine.  1940 =1940 = Invention of Modern Drug Discovery: Ehrlich & The Magic Bullet means compound that selectively targets a disease causing organism while having no negative effect on human tissue.no negative effect on human tissue.  1940 =First therapeutic use of penicillin by Floury.1940 =First therapeutic use of penicillin by Floury.  1944 = Selman waksman made Streptomycin from soil bacteria.1944 = Selman waksman made Streptomycin from soil bacteria.  1948 = Chlortetracycline.1948 = Chlortetracycline.  1957 = Nystatin (fungal infections)1957 = Nystatin (fungal infections)  1970’s = New 4-quinolones(pipemidic acid,oxolinic acid,cinoxacin)1970’s = New 4-quinolones(pipemidic acid,oxolinic acid,cinoxacin)  1980 =Norfloxacin, the first fluoroquinolone.1980 =Norfloxacin, the first fluoroquinolone.  1980 =Enroflocacin.1980 =Enroflocacin.  1998 =Smithkline Beecham patented Amoxicillin/clavulanate potassium tablets1998 =Smithkline Beecham patented Amoxicillin/clavulanate potassium tablets the first sold antibiotic under the trade names of Amoxil and trimox.the first sold antibiotic under the trade names of Amoxil and trimox.
  7. 7.  CLASSIFICATIONCLASSIFICATION :: Antibiotics are classified in many ways based on chemical structure, source,itsAntibiotics are classified in many ways based on chemical structure, source,its spectrum of activity and Mechanism of action (MOA).spectrum of activity and Mechanism of action (MOA).  *Based on the chemical structure:*Based on the chemical structure:  1.1.β-lactam antibioticsβ-lactam antibiotics : Penicillin's, Cephalosporin's, carbapenams, monobactams.: Penicillin's, Cephalosporin's, carbapenams, monobactams.  2.2. Amino glycoside antibioticsAmino glycoside antibiotics : Streptomycin, Neomycin, Kanamycin, Gentamycin, Tobramycin,: Streptomycin, Neomycin, Kanamycin, Gentamycin, Tobramycin, Amikacin.Amikacin.  3.3. TetracyclinesTetracyclines:: Tetracycline, Chlortetracycline, Oxytetracycline, Doxycycline, Minocycline,Tetracycline, Chlortetracycline, Oxytetracycline, Doxycycline, Minocycline, methacycline, meclocycline.methacycline, meclocycline.  4.4. Macrolide antibioticsMacrolide antibiotics :: (i.e., large macrolide structure)(i.e., large macrolide structure)::EryErythromycin,thromycin, ClariClarithromycin,thromycin, AziAzithromycinthromycin,, RoxiRoxithromycin.thromycin.  55.. PolypeptidePolypeptide antibioticsantibiotics : Actinomycin, Bacitracin, Colistin, Polymyxin B, tyrothricin: Actinomycin, Bacitracin, Colistin, Polymyxin B, tyrothricin  6.6. Polyenes:Polyenes: Amphotericin B, Nystatin.Amphotericin B, Nystatin.  7.7. Lincomycin:Lincomycin: Clindamycin.Clindamycin.  8.8. MiscellaneousMiscellaneous: Chloramphenical, Novobiocin, Mupirocin, Fucidic acid.: Chloramphenical, Novobiocin, Mupirocin, Fucidic acid.  *Based on the source*Based on the source :: They are divided in toThey are divided in to  Natural antibioticsNatural antibiotics :: Penicillium chrysogenum-Penicillium chrysogenum---- Penicillin.--- Penicillin.  Bacillus subtilisBacillus subtilis --------------- Bacitracin.--------------- Bacitracin.  Bacillus polymyxaBacillus polymyxa ------------- Polymyxin.------------- Polymyxin.  Stryptomyces griseus-Stryptomyces griseus---------- Stryptomycin.--------- Stryptomycin.  Streptomyces aureofaciensStreptomyces aureofaciens ---Chlortetracyclines---Chlortetracyclines  Streptomycers erythreusStreptomycers erythreus -------Erythromycin-------Erythromycin  Streptomyces venezulae-Streptomyces venezulae------- Chloramphenicol.------ Chloramphenicol.  Semisynthetic antibioticsSemisynthetic antibiotics : These antibiotics are commercially synthesized by adding chemical: These antibiotics are commercially synthesized by adding chemical compounds, amides etc., to the natural antibiotics. In these the main part of the chemical structure iscompounds, amides etc., to the natural antibiotics. In these the main part of the chemical structure is obtained from the micro-organisms which are then modified by adding various chemical moieties as the sideobtained from the micro-organisms which are then modified by adding various chemical moieties as the side chain.chain.  Ex:Ex: Ampicillin, Amoxacillin, Oxacillin, Cloxacillin, Dicloxacillin, Carbencillin. Methicillin.Ampicillin, Amoxacillin, Oxacillin, Cloxacillin, Dicloxacillin, Carbencillin. Methicillin.  **Spectrum ActivitySpectrum Activity ::  Broad spectrumBroad spectrum: These antibiotics inhibit the growth of wide range (i.e. More than one species) of: These antibiotics inhibit the growth of wide range (i.e. More than one species) of microorganisms. Some antibiotics can inhibit both Gram- positive and Gram-negative bacteria.microorganisms. Some antibiotics can inhibit both Gram- positive and Gram-negative bacteria.  EX:EX: Cephalosporins, Chloramphenicol, Tetracycline’sCephalosporins, Chloramphenicol, Tetracycline’s..  Narrow spectrumNarrow spectrum:: These antibiotics are effective mainly against a single species of microorganism eitherThese antibiotics are effective mainly against a single species of microorganism either  Gram +ve (or) Gram –ve bacteria. EX: -Gram +ve (or) Gram –ve bacteria. EX: - Bacitracin, Nystatin, PenicillinBacitracin, Nystatin, Penicillin..
  8. 8.  Antibiotic activityAntibiotic activity :Based on their activity against different m.o’s they are divided in to:Based on their activity against different m.o’s they are divided in to  a. Antibacterial antibiotics:a. Antibacterial antibiotics: The chemotherapeutic agents which kill or inhibit the growth of bacteriaThe chemotherapeutic agents which kill or inhibit the growth of bacteria  are called antibacterial antibiotics. (penicillins, cephalosporins, tetracyclines, aminoglycosides)are called antibacterial antibiotics. (penicillins, cephalosporins, tetracyclines, aminoglycosides)  1.1. Bactericidal antibioticsBactericidal antibiotics :: These are more effective in killing harmful microorganisms particularlyThese are more effective in killing harmful microorganisms particularly bacterialbacterial species. (species. (Kill the bacteria directlyKill the bacteria directly)) ExamplesExamples are …..are ….. 22. Bacteriostatic antibiotics:. Bacteriostatic antibiotics: These are effective in abolishing or preventing the growth ofThese are effective in abolishing or preventing the growth of bacterial species. (bacterial species. ( stop the bacteria from growingstop the bacteria from growing ):): EX: Tetracyclines, Chloramphenicol, Clindamycin.EX: Tetracyclines, Chloramphenicol, Clindamycin. b.b. Antifungal antibioticsAntifungal antibiotics : Griseofulvin, Amphoterisin B, Nystatin.: Griseofulvin, Amphoterisin B, Nystatin. c .c . Anthelmintic agentsAnthelmintic agents : Ivermectin.: Ivermectin. d.d. Anticancer antibioticsAnticancer antibiotics : Bleomycin, Dactinomycin, Doxorubicin.: Bleomycin, Dactinomycin, Doxorubicin. Based on Mechanism of action (MOA) :Based on Mechanism of action (MOA) : Cell wall synthesis inhibitorsCell wall synthesis inhibitors : Penicillins, Cephalosporins, Carbapenams, Aztreonam.: Penicillins, Cephalosporins, Carbapenams, Aztreonam. Microbial cell membrane inhibitors :Microbial cell membrane inhibitors : Polymyxin B and E, Colistin, Polyene, Imidazole.Polymyxin B and E, Colistin, Polyene, Imidazole. Protein synthesis inhibitors:Protein synthesis inhibitors: Aminoglycosides, Macrolides, Tetracyclines.Aminoglycosides, Macrolides, Tetracyclines. Penicillins and Cephalosporins Are Very cidal For Microbes Penicillins Cephalosporins Aminoglycosides Vancomycin Fluoroquinolones Mietronidazole
  9. 9. Beta-lactam antibiotics will be examined in fourBeta-lactam antibiotics will be examined in four groups, includinggroups, including penicllinspenicllins, cephalosporins,, cephalosporins, monobactams, and carbapenems.monobactams, and carbapenems. The beta-lactam ring is joined to a five-memberedThe beta-lactam ring is joined to a five-membered thiazolidine ring in penicillin,thiazolidine ring in penicillin, Six-membered dihydrothiazine ring inSix-membered dihydrothiazine ring in cephalosporins.cephalosporins. In carbapenems, the beta-lactam ring is alsoIn carbapenems, the beta-lactam ring is also joined to a five-membered ring, although it isjoined to a five-membered ring, although it is carbocyclic.carbocyclic. Monobactams have a monocyclic betalactamMonobactams have a monocyclic betalactam structure, and the side sulfo-group is joined to astructure, and the side sulfo-group is joined to a nitrogen atom.nitrogen atom. All of these contain a four-membered beta-lactamAll of these contain a four-membered beta-lactam ring, which is necessary for exhibiting antibacterialring, which is necessary for exhibiting antibacterial activity.activity. Four groups Beta-lactam antibiotics
  10. 10.  Penicillin was discovered inPenicillin was discovered in 19281928 byby Alexander FlemingAlexander Fleming, who, who noticed that one of his experimental cultures ofnoticed that one of his experimental cultures of staphylococcusstaphylococcus was contaminated with mold, which caused the bacteria towas contaminated with mold, which caused the bacteria to lyse. Since mold belonged to the familylyse. Since mold belonged to the family PenicilliumPenicillium, he named, he named the antibacterialthe antibacterial substancesubstance penicillin.penicillin.  About a decade later, a group of researchers at OxfordAbout a decade later, a group of researchers at Oxford University isolated a crude substance made up of a few low-University isolated a crude substance made up of a few low- molecular substances, which were penicillins (molecular substances, which were penicillins (F, G, K, O, V,F, G, K, O, V, XX).). PENICILLINSPENICILLINS
  11. 11. Penicillium mould (penicillium notatum)
  12. 12. Historical background of penicillinsHistorical background of penicillins  Alexander Fleming was born in Loudon, Scotland on 6 August,Alexander Fleming was born in Loudon, Scotland on 6 August, 1881 in a farming family.1881 in a farming family.  He carried on his schooling atHe carried on his schooling at regent streetregent street polytechnicpolytechnic after hisafter his family moved to London in 1895.family moved to London in 1895.  He joinedHe joined St. Mary's medical schoolSt. Mary's medical school and became research assistantand became research assistant to renowned Sir Almroth Wright, after he gotto renowned Sir Almroth Wright, after he got distinctiondistinction in 1906.in 1906.  He completed his degreeHe completed his degree (M.B.B.S.)(M.B.B.S.) withwith gold medalgold medal in 1908 fromin 1908 from the University of London and lectured at St. Mart till 1914.the University of London and lectured at St. Mart till 1914.  He served asHe served as captaincaptain during theduring the World War IWorld War I and worked inand worked in battlefield hospitals in France. After the war he returned to St. Marybattlefield hospitals in France. After the war he returned to St. Mary in 1918 and got elected asin 1918 and got elected as Professor of bacteriology in 1928.Professor of bacteriology in 1928.  He discovered natural antiseptic enzyme in 1921, which he namedHe discovered natural antiseptic enzyme in 1921, which he named lysozymelysozyme. This substance existed in tissues and secretions like. This substance existed in tissues and secretions like mucus, tears and egg-white but it did not have much effect on themucus, tears and egg-white but it did not have much effect on the strongly harmful bacteria.strongly harmful bacteria.  It was in 1928 when he observed while experimenting onIt was in 1928 when he observed while experimenting on influenzainfluenza virusvirus that a common fungus inhibiting the growth of organism.that a common fungus inhibiting the growth of organism.
  13. 13.  It was aIt was a Serendipitous observation(fortuitous accident)Serendipitous observation(fortuitous accident) i.e (happeningi.e (happening by chance) in his laboratory in the basement of St. Mary's Hospital inby chance) in his laboratory in the basement of St. Mary's Hospital in London ( now part of imperical college).London ( now part of imperical college).  On Friday, September 28, in 1928, Fleming left the lid off of one ofOn Friday, September 28, in 1928, Fleming left the lid off of one of his Petri dishes for several weeks, and a fungal spore landed on it (thehis Petri dishes for several weeks, and a fungal spore landed on it (the culture became contaminated). After returning from vacation, Flemingculture became contaminated). After returning from vacation, Fleming noticed that hisnoticed that his StaphylococcusStaphylococcus culture was contaminated with thisculture was contaminated with this fungus but instead of throwing the Petri dish away, hefungus but instead of throwing the Petri dish away, he carefullycarefully examined it first.examined it first.  There was an inhibited bacterial growth around the mould. FlemingThere was an inhibited bacterial growth around the mould. Fleming concluded that the mould (fungal colony) was releasing aconcluded that the mould (fungal colony) was releasing a antibacterial substance which was spreading into the surrounding areaantibacterial substance which was spreading into the surrounding area where the bacterial colonies were dying. i.e. lysing the bacteria.where the bacterial colonies were dying. i.e. lysing the bacteria.  He grew a pure culture and discovered that it was aHe grew a pure culture and discovered that it was a PenicilliumPenicillium mould, now known to bemould, now known to be Penicillium notatum.Penicillium notatum.  Penicillium mould must be secreting an antibacterial substance,Penicillium mould must be secreting an antibacterial substance, which he isolated first in crude form of the active substance andwhich he isolated first in crude form of the active substance and named it as penicillin.named it as penicillin.
  14. 14.  This newly discovered active substance(penicillin) was effectiveThis newly discovered active substance(penicillin) was effective even when diluted up toeven when diluted up to 800800 times.times.  Unfortunately, the substance was alsoUnfortunately, the substance was also unstable and Fleming wasunstable and Fleming was unableunable to isolate and purify the compoundto isolate and purify the compound. He therefore came to. He therefore came to the conclusion that penicillin was too unstable to be used clinically.the conclusion that penicillin was too unstable to be used clinically.  Florey and Chain in 1938Florey and Chain in 1938 by using processes such asby using processes such as freeze-dryingfreeze-drying and chromatographyand chromatography which allowed isolation of pure form ofwhich allowed isolation of pure form of penicillins.penicillins.  Fleming, Florey, and Chain shared theFleming, Florey, and Chain shared the 1945 Nobel Prize1945 Nobel Prize for theirfor their medicinal work on penicillin.medicinal work on penicillin.  In june 1942 availability of penicillin was just to treat 10 patients.In june 1942 availability of penicillin was just to treat 10 patients.  After fermentation research 2.3 million doses had been increased inAfter fermentation research 2.3 million doses had been increased in U.S.U.S.
  15. 15. Commercial production of antibioticsCommercial production of antibiotics The general scheme may be divided into six stepsThe general scheme may be divided into six steps 1.1. Preparation of a pure culture of the desired organism for use in inoculation of thePreparation of a pure culture of the desired organism for use in inoculation of the fermentation medium.fermentation medium. 2.2. Fermentation, during which the antibiotic is formed.Fermentation, during which the antibiotic is formed. 3.3. Isolation of the antibiotic from the culture medium.Isolation of the antibiotic from the culture medium. 4.4. Purification.Purification. 5.5. Assays for potency, sterility, absence of pyrogens, and other necessary data.Assays for potency, sterility, absence of pyrogens, and other necessary data. 6.6. Formulation into acceptable and stable dosage forms.Formulation into acceptable and stable dosage forms. 1943 the mass production of penicillin began. As the production increased the cost dropped Correspondingly. When penicillin was first available, 100,000 units sold for $20. currently, the same quantity costs less than a penny
  16. 16.  Once the penicillin is released from the fungal cells, the compoundOnce the penicillin is released from the fungal cells, the compound is isolated from the fermenter's contents and purified by specialis isolated from the fermenter's contents and purified by special biochemical processes.biochemical processes.  Such commercial production results in more than 100,000,000Such commercial production results in more than 100,000,000 pounds of penicillin production per year.pounds of penicillin production per year. Bulk production of pencillins
  17. 17. Biological sources of penicillinBiological sources of penicillin  The first naturally occurring benzyl penicillin (penicillin G is alsoThe first naturally occurring benzyl penicillin (penicillin G is also referred to asreferred to as gold standard penicillingold standard penicillin ) was obtained by the) was obtained by the fermentation of fungusfermentation of fungus Penicillium notatumPenicillium notatum..  At present it is obtained from a highly yielding strain calledAt present it is obtained from a highly yielding strain called PenicilliumPenicillium chrysogenumchrysogenum and other penicillum species.and other penicillum species.  30 different biosynthetic penicillin's have been isolated from various30 different biosynthetic penicillin's have been isolated from various strains ofstrains of Penicillium notatiumPenicillium notatium andand Penicillum chrysogenum.Penicillum chrysogenum.
  18. 18. 5 Classes of Penicillins Natural Penicillins (Fermentation derived penicillins) Penicillin G ,Penicillin V Semi synthetic Penicillinase Resistant Penicillins (parenteral) Methicillin Nafcillin Isoxazolyl Penicillins (Cloxacillin / Dicloxacillin / Oxacillin / Flucloxacillin) Amino penicillins ( Semisynthetic penicillinase sensitive broad spectrum penicillins) Ampicillin , Amoxicillin Carboxy penicillins ( Synthetic penicillins sensitive to broad spectrum, Parenteral penicillins.) Carbencillin, Carbencillin phenyl, Carbencillin indanyl. Ticarcillin Ureidopenicillins Piperacillin , Mezlocillin, Azlocillin
  19. 19. R =
  20. 20. STRUCTURE OF PENICILLINS
  21. 21. Penicillin G (Benzylpenicillin)Penicillin G (Benzylpenicillin)  Penicillin G is also referred to asPenicillin G is also referred to as gold standard penicillingold standard penicillin..  Penicillin G is not acid resistant it is acid sensitive.Penicillin G is not acid resistant it is acid sensitive.  3 reasons for the acid sensitivity of penicillin G.3 reasons for the acid sensitivity of penicillin G.  11.. Ring strainRing strain. ( 4 membered betalactam ring + 5 membered thiazolidine ring) As a result penicillins. ( 4 membered betalactam ring + 5 membered thiazolidine ring) As a result penicillins suffers large angle and torsional strains. Acid catalyzed ring opening relieves these strains by breakingsuffers large angle and torsional strains. Acid catalyzed ring opening relieves these strains by breaking open the more highlyopen the more highly ββ –lactam ring.–lactam ring.  22.. Highly reactive corbonyl groupHighly reactive corbonyl group.. The resonance stabilization is impossible for theThe resonance stabilization is impossible for the ββ –lactam ring because–lactam ring because of the increase in angle strain that would result in having a double bond withinof the increase in angle strain that would result in having a double bond within ββ –lactam ring. So the–lactam ring. So the angle of theangle of the ββ –lactam ring constrained to 90–lactam ring constrained to 9000 . So the lone pair is localized on the N atom, and the. So the lone pair is localized on the N atom, and the carbonyl group is more electrophilic than one would expect for a tertiary amide.carbonyl group is more electrophilic than one would expect for a tertiary amide.  Influence of the acyl side chainInfluence of the acyl side chain: Acyl group open up the lactam ring . So Penicillin G has a self-destruct: Acyl group open up the lactam ring . So Penicillin G has a self-destruct mechanism built in its structure.mechanism built in its structure. Benzylpenicillin is broken down by stomach acidBenzylpenicillin is broken down by stomach acid and destroyed by staphylococcus penicillinase.and destroyed by staphylococcus penicillinase. So it can be given by IV.So it can be given by IV. Therapeutic uses: Drugs of the penicillin group are effective for infections caused by Gram-positive bacteria (streptococcus, pneumococcus, and others), spirochaetae, and other pathogenic microorganisms. Drugs of this group are ineffective with respect to viruses, mycobacteria tuberculosis, fungi, and the majority of Gram-negative microorganisms. Benzylpenicillin is the drug of choice for infections caused by sensitive organisms. This includes streptococci infections (except enterococci), gonococci, and meningococci that do not produce beta-lactam anaerobes. Benzylpenicillin is used for croupous and focal pneumonia, skin infections, soft tissue and mucous membranes, periotonitis, cystisis, syphilis, diphtheria, and other infectious diseases. Benzyl group N S COOH H CH3 CH3 HH O HNCH2C O
  22. 22. N S COOH H CH3 CH3 HH O HNCH2C O O It withdraws the electrons away from the corbonyl oxygen and reduce the tendency to act as a nucleophile Phenoxy methyl Penicillin ( Penicilln V) •By placing electron with drawing group in the side chain which could draw electrons away from the corbonyl oxygen and reduce its tendency to act as a nucleophile. •Penicillin- V has electro –ve oxygen on the acyl side chain with electron withdrawing effect. It has more acid stability than penicillin G . •It is more stable in acid in the stomach, so it can be given orally. •Infact acid sensitivity can be solved by having an electron withdrawing group on the Acyl side chain. PENICILLIN- V
  23. 23. N S COOH H CH3 CH3 HH O HNCH2C O OCH3 OCH3 Strategy is putting two ortho- methoxy groups on the aromatic ring. Bulky groups "Steric shields” can be added to penicillins to protect them from bacterial Betalactamase (peicillinase) enzymes. By placing bulky groups on the side chain, bulky groups can prevent the betalactamase or penicillinase enzyme to Reach the beta lactamase or penicillinase active site. Because of betalactamases bacteria can gain resistance to penicillin. Betalactamases hydrolyse the ester link and open the pencillin. 1000 penicillin molecules are hydrolysed per second. Infact steric shield should not be too bulkey. If it is too bulkey it also prevents the penicillin from attacking the transpeptidase target enzyme. It should not be too small enough.. Methicillin is also not a ideal drug. Infact methicillin has no electron withdrawing group on the side chain. Methicillin is acid sensitive and has to be injected. Penicillinase resistant penicillins METHICILLIN OC2H5 R Group Nafcillin. (Narrow spectrum Antistaphylococcal penicillins) Methicillin in USA not ued clinically Methicillin produces Interstitial Nephritis (damages the kedney). Nafcillin also some times produces Interstitial Nephritis. it also Produces Neutropenia (Low level of Neutrophils)
  24. 24. Isoxazoyl Penicillins Penicillinase- resistant penicillins or β- lactamase- resistant penicillins R1 R2 Oxacillin H H Cloxacillin Cl H Dicloxacillin Cl Cl Flucloxacillin Cl F N S CH3 CH3 COOH O HN O N O CH3 R1 R2 H H H Bulkyand electron withdrawing group Isoxazolyl ring The incorporation of an isoxazolyl ring in to the penicillin side chain lead to orally active compounds which were stable to β-lactamase enzymes of S. aureus. The isoxazolyl ring acts as the steric shiels but it is also electron-withdrawing, giving the structure acid stable. The β-Lactamase resistant penicllins tend to be comparatively lipophilic molecules that do not penetrate well into Gram –ve bacteria. α- acyl carbon could be part of an aromatic ( phenyl or Naphthyl or heteroaromatic (e.g., 4-isoazoyl) system.
  25. 25.  To sum up acid resistant penicillins would be the drugs of first choice against an infection.  If the bacteria proved resistance due to the presence of a Penicillinase enzyme  Penicillin resistant S. aureus therapy would be changed to penicillinase resistant penicillins.  Hydrophobic groups on the side chain(pen-G) favor gram +ve but Poor activity against gram- ve.  Enhancement of gram -ve activity is found if hydrophilic Groups – NH2, - OH, -COOH are attached to the alpha carbon from the carbonyl group on the side chain. Those Penicillins have useful activity against gram +ve and gram -ve.  Hydrophilic groups on the side chain have little effect on Gram-positive activity (e.g. penicillin T) or cause a reduction of activity (e.g. penicillin N)  However, they lead to an increase in activity against Gram-negative bacteria.
  26. 26. The acidic stability of the ampicillin also attributes the electron withdrawing character of the primary amino group which prevents the hydrolysis of the β-lactum bond. It is susceptible to degradation by β-lactamase enzymes. Hence it is given in Combination with inhibitors like sulbactum. Hydrophobic groups on the side chain( Ex: penicillin G) favor activity against Gram-positive bacteria Hydrophilic groups on the side chain have increase in activity against Gram –negative bacteria. If the hydrophilic group is (NH2,OH,COOH group) attached to the carbon, alpha to the carbonyl group on the side chain. All have an alpha hydrophilic group which aids the passage of these penicillins through the porins of the Gram-ve Bacterial outer cell membrane. Uses: Ampicillin and Amoxicillin HELPS to clear the Enterococci. H – Haemophilus Influenzae. E – Escherichia Coli. L – Listeria monocytogenes. P- Proteus. S – Salmonella Typhi. Amino Penicillins ( Ampicllin, Amoxicillin ) AMPICILLIN N S CH3 CH3 COOH O HN O C H H H NH2 H It is used for bronchitis, pneumonia, dysentery, salmonella, whooping cough, pyelonephritis, endocarditis, sepsis, and so on.
  27. 27. Amoxicillin (Amoxil) (p-hydroxy Ampicillin) Amoxicillin is the very similar in structure like ampicillin, the only difference being an extra phenol group on amoxicillin. *similar spectrum of activity to penicillin G, but more active against Gram-ve bacteria *Acid resistant due to the –NH2 group and therefore orally active. *Non toxic, *Sensitive to β-lactamase (No shield). ---Can cause diarrhea due to poor absorption through the gut wall, is due to dipolar nature of the molecule It has both free carboxylic acid and amino function. This problem can be solved by using a prodrug Pivampicillin, talampicillin, bacampicillin are prodrugs of ampicillin. acyloxymethyl esters are used to mask the -COOH groups. Its spectrum of activity is increased when administered with clavalunic acid. Amoxicillin + clavalunic acid = Augmentin tablets. Broad spectrum activity is associated with the presence of an alpha hydrophilic group on the acyl side chain of penicillin. Extra phenol group is present on amoxicillin. If you compare with ampicillin, amoxicillin Is better absorbed through gut wall. Uses: Bronchitis Pneumonia Typhoid Enteric fever Gonorrhoea Urinary tract infactions. N S CH3 CH3 COOH O HN O C H H H NH2 H HO
  28. 28. Ampicillin synthesis: Directly acylating 6-APA with phenylglycine chloride hydrochloride Ampicillin Amoxicillin synthesis: The direct reaction of D-(-)-2-(4-hydroxyphenyl) glycine chloride hydrochloride with trimethylsylil ester of 6-APA Amoxicillin
  29. 29. Nomenclature of PenicillinsNomenclature of Penicillins Nomenclature of penicillins was done in different systemsNomenclature of penicillins was done in different systems.. Chemical abstract system(CAS): •According to this system penicillins are numbered starting from “S” atom. Sulphur atom is assigned the 1st position and “N” atom is assigned number 4. 1 2 34 56 7 Bicyclic ring system 6- Acyl amino-2,2-dimethyl-3- carboxylic acid United States Pharmacopoeia (USP system): •The USP system of naming penicillins is the reverse of CAS. •According to this system the nitrogen atom is given the 1st position and “S” atom is assigned the 4th position. 1 2 3 4 56 7 4-thia-1-azabicyclo [3.2.0] heptane 1 22 34 56 7 1 2 3 4 56 7
  30. 30. As derivatives of Penam: Unsubstituted bicyclic system together with amide corbonyl group has been named as penam. According to this method penicillins are named as 4- Thia-1-azabicyclo[3.2.0] heptane-7-one. 4. As derivatives of penicillanic acid: In this method penicillins are named as derivatives of penicillanic acid ring system with 6- acyl amino -2,2-dimethyl penam -3- carboxylic acid. 1 5. As derivatives of penicillins (on the basis of “R” group) … TRIVAL SYSTEM In this system 6-corbonyl amino penicillanic acid portion of the molecule is named as penicillin and the different penicillins are distinguished on the basis of “R” group on the acyl amino side chain. 4 56 7 This system of naming of penicillins is simple and serves as a good measure for naming and comparing closely related penicillin structures. However this system is not well suited for compounds having the
  31. 31. Stereo chemistryStereo chemistry The penicillin molecule contains three chiral carbon atoms at C-3, C-5 andThe penicillin molecule contains three chiral carbon atoms at C-3, C-5 and C-6.C-6.  All natural and synthetic penicillins have the same absolute configurationAll natural and synthetic penicillins have the same absolute configuration about these three centers.about these three centers.  The 6The 6thth carbon atom bearing the acyl amino group has the L-configuration,carbon atom bearing the acyl amino group has the L-configuration, where as the carbon to which the carboxyl group was attached has thewhere as the carbon to which the carboxyl group was attached has the D- configuration.D- configuration.  Thus the acyl amino group and carboxyl group are trans to each other, withThus the acyl amino group and carboxyl group are trans to each other, with the formerthe former αα and latter in theand latter in the ββ orientation relative to penam ring.orientation relative to penam ring.  The absolute stereochemistry of the penicillins was designated asThe absolute stereochemistry of the penicillins was designated as 3S:5R:6R.3S:5R:6R.  The atoms composing the 6-aminopenicillanic acid are biosyntheticallyThe atoms composing the 6-aminopenicillanic acid are biosynthetically derived from two amino acids, L-cysteine and D-valine.derived from two amino acids, L-cysteine and D-valine.
  32. 32. Reactions: Hydrolysis of penicillins by hot and cold dilute mineral acidReactions: Hydrolysis of penicillins by hot and cold dilute mineral acid
  33. 33. There are also a variety of acylases that have been isolated from some bacteria, and these enzymes cleave the acylamino sidechain of the antibiotic, a modification which also
  34. 34. N S COO H CH3 CH3 HH O HNCR O Thiazolidine ring β-Lactam ring Cis orientation of hydrogens (stereochemistry) are essential Bicyclic system essential Free corboxylate essential Amide essential or acylaminoside chain essential Strained β-lacturm ring,which is necessary for exhibiting antibacterial activity (The corboxylate ion binds to the charged ammonium ion of a lysine residue in the binding site) Sulfur is usual but not essential Presence of one α-orientation and one β-orientation is essential for activity Presence of N is essential any modification upon nitrogen it will results lack of activity. Highly reactive ketonic group at 7th position also essential any modification lack of activity. Amino group present on the 6th position should be trans which is very essential. 1 2 34 56 7 Bicyclic system confers further strainon β-lactam ring. Greater the stran, the greater the activity,but greater the instability of the molecure to other factors. 6-Aminopenicillanic acid The “R”group determines the Stability and Improved spectrum of activity and Pharmacokinetic advantages. BASIC CHEMISTRY= β-LACTRUM RING + THIAZOLIDINE RING STRUCTURE - ACTIVITY RELATION SHIP (SAR) OF PENICILLINS GENERAL STUCTURE OF PENICILLIN OR PENICILLIN CORE STRUCTURE PENICILLIN NUCLEUS OR BASIC STRUCTUREOF PENICILLIN Valine (amino acid) By Prof. Ravisankar Site of penicillinase action(break in beta lactum ring (that bond is broken by betalactamase or penicillinase Enzyme.(the bond b/n C and N is broken by ß-lactamase (or) penicillinase enzme. Cysteine
  35. 35. Key features of structure  1. β-lactam ring  a. "Lactam" is a word for any cyclic amide (the word "lactone" is used for a cyclic ester)  b. a β-lactam means that the nitrogen is joined to the carbon which is beta to the carbonyl  c. this creates strain in the ring, since it is a four membered ring  d. b-lactam becomes good acylating agent for active site serine of penicillin binding  protein  2. Carboxylate:  a. Negatively charged at neutral pH  b. Anchors drug in active site pocket (positively charged)  3. Acylamide side chain:  a. Necessary for biological potency  b. Proper stereochemistry of attachment to ring essential for activity  c. Variation at side chain can dramatically affect biological activity against various strains of bacteria  D. Common Early Penicillins  1. Penicillin G had to be administered parenterally, since it isn't acid stable.  2. Penicillin V has more acid stability, and can be administered orally
  36. 36. Penicillins are…. a group of antibiotics that contain 6-amino penicillanic acid side chain attached to the 6-amino group. •The penicillin nucleus is the chief structural requirement for biological activity. •The side chain structure determines the many of the antibacterial and pharmacological characterstics. •The strained β-lactum ring is essential. •Penicillin contains β-lactum ring is fused with thiazolidine ring. •The free carboxylic acid is essential. The carbolated ion is binds to the charged ammonium ion of lysine residue in the binding site. •The bicyclic system is important. The greater the strain, the greater the activity. •The acyl amino side chain is essential. •Sulfur is usual but not essential. •The cis- stereo chemistry of bicyclic ring with respect to the acyl amino side chain is important. •Oxidation of sulphur to a sulfone or sulfoxide will decrease the activity. •The methyl groups at position 2 are essential. •β- lactum corbonyl group at position “7” is must. •The carboxylic acid is changed to an alcohol or ester activity is decreased. •“N” at position 4 is must for antibacterial activity. •Penicillin molecule contains a ‘3’ chiral carbon atome c-3,c-5,c-6. Disruption of •These spacial arrangements results in loss of activity.
  37. 37.  SAR of “R” group:SAR of “R” group:  C-6 amino west end substitution:C-6 amino west end substitution: The design and development of the west-end substituents hasThe design and development of the west-end substituents has been aimed at strengthening of activity, stability, resistance, absorption and distribution.been aimed at strengthening of activity, stability, resistance, absorption and distribution.  Placing the electron withdrawing group in the side chain which could draw electrons awayPlacing the electron withdrawing group in the side chain which could draw electrons away from the carbonyl oxygen and reduce the tendency to act as a nucleophile and allows afrom the carbonyl oxygen and reduce the tendency to act as a nucleophile and allows a greater stability and oral availability. Ex: penicillin V, Ampicillin.greater stability and oral availability. Ex: penicillin V, Ampicillin.  Stereic shields can be added to penicillin to protect them from bacterial β-lactamase enzymes.Stereic shields can be added to penicillin to protect them from bacterial β-lactamase enzymes.  By placing bulky groups on the side chain it prevent the penicillin from entering theBy placing bulky groups on the side chain it prevent the penicillin from entering the penicillinase or β-lactamase active site.penicillinase or β-lactamase active site.  Infact if the stereic shield was too bulky then it also prevents the penicillin fromInfact if the stereic shield was too bulky then it also prevents the penicillin from attacking the transpeptidase target enzyme, It should be ideal shield.attacking the transpeptidase target enzyme, It should be ideal shield. but it should not be too small enough…but it should not be too small enough… Ex: Methicillin.Ex: Methicillin.  Indeed Methicillin has no electron with drawing group on the side chain. It is acid sensitiveIndeed Methicillin has no electron with drawing group on the side chain. It is acid sensitive and has to be injected.and has to be injected.  Incorporation of isoxazolyl ring in to the penicillin side chain lead to the development ofIncorporation of isoxazolyl ring in to the penicillin side chain lead to the development of better penicillinase resistant agents. In fact isoxazolyl ring acts as the stereic shield but alsobetter penicillinase resistant agents. In fact isoxazolyl ring acts as the stereic shield but also electron withdrawing group giving the structure acid stability.electron withdrawing group giving the structure acid stability. Ex: Oxacillin, Cloxacillin, Dicloxacillin, Flucloxacillin.Ex: Oxacillin, Cloxacillin, Dicloxacillin, Flucloxacillin.
  38. 38.  Broad spectrum activity is associated with the presence ofBroad spectrum activity is associated with the presence of αα-hydrophilic-hydrophilic group on the acyl side chain of penicillin.group on the acyl side chain of penicillin.  Enhancement of Gram –ve activity is increased hydrophilic groupEnhancement of Gram –ve activity is increased hydrophilic group (-NH(-NH22,OH,-COOH group), attached to the Carbon,,OH,-COOH group), attached to the Carbon,αα to the carbonyl groupto the carbonyl group on the side chain. These penicillin's are having useful activity against bothon the side chain. These penicillin's are having useful activity against both remove and gram-Vet bacteria are known as broad spectrum antibiotics.remove and gram-Vet bacteria are known as broad spectrum antibiotics. EX: Ampicillin and Amoxicillin.EX: Ampicillin and Amoxicillin.  The spectrum of activity was further extended with introducing strongThe spectrum of activity was further extended with introducing strong acidic group is attached to the carbonacidic group is attached to the carbon αα- to the carbonyl group on the side- to the carbonyl group on the side chain.chain. αα - carboxy penicillins are broad spectrum penicillins and wider range of- carboxy penicillins are broad spectrum penicillins and wider range of gram-ve activity than ampicillin.gram-ve activity than ampicillin. EX: Carbencillin,Ticarcillin.EX: Carbencillin,Ticarcillin.  The acylation of the ampicillin west-end amine functionality withThe acylation of the ampicillin west-end amine functionality with certain polar groups leads to cyclic urea derivatives.certain polar groups leads to cyclic urea derivatives.  Urido penicillins have a urea functional group atUrido penicillins have a urea functional group at αα-position. In fact they-position. In fact they are more active than the carboxy Penicillins against streptococci andare more active than the carboxy Penicillins against streptococci and Haemophilus species. Presence of urea group gives improved penetrationHaemophilus species. Presence of urea group gives improved penetration in to gram-ve species.in to gram-ve species. EX: Azocillin, Mezlocillin, Piperacillin.EX: Azocillin, Mezlocillin, Piperacillin.
  39. 39. Plasma membrane Peptidoglycan cell wall (rigid coating around the membrane) Lipopolysaccharide layer (LPS) Gram +ve Gram –ve Thick Thin One of the major difference between 2 types of bacteria is the amount of peptidoglycon They have on the cell wall. Gram +ve bacteria has a lot of peptidoglycon and this actually holds the gram stain in That’s why it is gram +ve. Gram –ve bacteria has a very thin layer of the peptidoglycon and gram stain leaks out Cell membrane (or) Outer membrane Since the penicillin's inhibits peptidoglycon synthesis it is much better an attacking gram+ve bacteria such as Staphylococci, and streptococci than gram –Ve bacteria like E-coli.
  40. 40. Beta-lactam antibiotics are relativelyBeta-lactam antibiotics are relatively non-toxic to humans why?non-toxic to humans why?  One of the important point is penicillin is acting as a mimicOne of the important point is penicillin is acting as a mimic for a D-Ala-D- Ala moiety, this provides another explanationfor a D-Ala-D- Ala moiety, this provides another explanation for its lack of toxicity.for its lack of toxicity.  There is no D-Ala- D-Ala amino acids or D-Ala- D-AlaThere is no D-Ala- D-Ala amino acids or D-Ala- D-Ala segments in any human protein. That’s why any of the body'ssegments in any human protein. That’s why any of the body's serine protease enzymes does not recognize penicillin.serine protease enzymes does not recognize penicillin.  As a result penicillin is only selective for bacterialAs a result penicillin is only selective for bacterial transpeptidase enzyme and ignored by the body’s own serinetranspeptidase enzyme and ignored by the body’s own serine protease.protease.
  41. 41. Mechanism of action of penicillinsMechanism of action of penicillins  The primary mechanism of the action of beta-lactam antibiotics is the inhibition of synthesis ofThe primary mechanism of the action of beta-lactam antibiotics is the inhibition of synthesis of cell walcell wall ofl of bacteria, which causes them to quickly die.bacteria, which causes them to quickly die.  The cell membrane protects bacteria cells from lysis, which can occur as a result of different osmotic pressuresThe cell membrane protects bacteria cells from lysis, which can occur as a result of different osmotic pressures between the cytoplasm and the surrounding medium..between the cytoplasm and the surrounding medium..  The main component of bacterial cell membranes is a mixed polymer known asThe main component of bacterial cell membranes is a mixed polymer known as murein or peptidoglycanmurein or peptidoglycan.. Peptidoglycon is a long polysaccharide chain that is cross-linked with short peptides.Peptidoglycon is a long polysaccharide chain that is cross-linked with short peptides.  Polysaccharide chains are made up of two varying aminosugars—Polysaccharide chains are made up of two varying aminosugars—N-acetylglucosamineN-acetylglucosamine andand N-acetylmuraminic acidN-acetylmuraminic acid. There are significant differences between Gram +ve and Gram –ve bacteria. The. There are significant differences between Gram +ve and Gram –ve bacteria. The cell wall in Gram +ve bacteria consists ofcell wall in Gram +ve bacteria consists of 50-10050-100 peptidoglycon layers where as Gram –ve bacteria itpeptidoglycon layers where as Gram –ve bacteria it consists onlyconsists only 2 layers2 layers..  Beta-lactam antibiotics specifically bind with a number of proteins of cytoplasmic membranes known asBeta-lactam antibiotics specifically bind with a number of proteins of cytoplasmic membranes known as penicillin-binding proteins (PBP).penicillin-binding proteins (PBP).  The enzyme responsible for the cross-linking reaction is known as theThe enzyme responsible for the cross-linking reaction is known as the transpeptidase enzyme.transpeptidase enzyme.  Beta-lactam antibiotics must pass through the outer layer of the cell in order to get the desired PBP to theBeta-lactam antibiotics must pass through the outer layer of the cell in order to get the desired PBP to the surface of the membrane.surface of the membrane.  About 30 enzymes are involved in the overall biosynthesis of cell wall but final cross linking reaction which isAbout 30 enzymes are involved in the overall biosynthesis of cell wall but final cross linking reaction which is inhibited by penicillin. This leads to a cell wall framework that is no longer interlinked. As a result, the wallinhibited by penicillin. This leads to a cell wall framework that is no longer interlinked. As a result, the wall becomes fragile and can no longer prevent the cell frombecomes fragile and can no longer prevent the cell from swelling and bursting.swelling and bursting.  It has been proposed thatIt has been proposed that penicillin has a conformation which is similarpenicillin has a conformation which is similar to the transition state conformationto the transition state conformation taken up by thetaken up by the D-Ala- D-Ala moietyD-Ala- D-Ala moiety during cross linking reaction. The enzyme mistakes penicillin for D-during cross linking reaction. The enzyme mistakes penicillin for D- Ala- D-Ala and binds to the active site.Ala- D-Ala and binds to the active site.  Once bound, penicillin is subjected toOnce bound, penicillin is subjected to nucleophilic attack by serinenucleophilic attack by serine. The enzyme can attack the. The enzyme can attack the ββ- lactam rung- lactam rung of penicillin and open it in the same way as it did with the peptide bond. However penicillin is a cyclic and asof penicillin and open it in the same way as it did with the peptide bond. However penicillin is a cyclic and as a result the molecule isa result the molecule is not split in twonot split in two and nothing leaves the active site.and nothing leaves the active site.
  42. 42.  Transpeptidase connects the little peptide chains perpendicular to the NAM chains.Transpeptidase connects the little peptide chains perpendicular to the NAM chains.  Without the grid the rapidly growing bacteria can’t maintain the strong cell wall.Without the grid the rapidly growing bacteria can’t maintain the strong cell wall.  There is a high pressure inside the cell i.e. 10-20 atm. pressure which means if the cell wall isThere is a high pressure inside the cell i.e. 10-20 atm. pressure which means if the cell wall is not present, the rigid coating bacteria can swell and burst.not present, the rigid coating bacteria can swell and burst.  β – lactam antibiotics like penicillins act by inhibiting the transpeptidase (or) PBPs byβ – lactam antibiotics like penicillins act by inhibiting the transpeptidase (or) PBPs by covalently bonding to the serine residues within the active sites and prevent the cell wallcovalently bonding to the serine residues within the active sites and prevent the cell wall synthesis.synthesis.
  43. 43. (Peptidoglycan cell wall) N-acetylglucosamine N-acetylmuramic acid Transpeptidase located within the cell membrane are responsible for cross linking the Peptidoglycon chains Transpeptidases (Penicillin Binding Proteins) In order to make the rigid grid, There is an enzyme called Transpeptidase, which connects the Little peptide strings perpendicular to the NAM and NAG chains. Cell membrane PBP’S (or) transpeptidase help to build Or construct maintain the peptidoglycon Layer.
  44. 44. Cross-linking of bacterial cell walls inhibited by penicillin
  45. 45.  Sugars contained in the cell wall structure of bacteria.Sugars contained in the cell wall structure of bacteria.  N-acetylglucosamine (NAG)N-acetylglucosamine (NAG)  N- acetylmuramic acid (NAM)N- acetylmuramic acid (NAM) PEPTIDOGLYCAN STRUCTURE OF BACTERIAL CELL WALLS
  46. 46. Mechanisms of transpeptidase crosslinking and penicillin inhibition.
  47. 47.  Microbial resistance toMicrobial resistance to ββ-lactam antibiotics-lactam antibiotics like penicillins, cephalosporins occurslike penicillins, cephalosporins occurs mainlymainly due to the production of an enzyme known asdue to the production of an enzyme known as ββ-lactamases.-lactamases.  ββ-lactamases act by breaking the-lactamases act by breaking the ββ-lactam ring by catalyzing the hydrolysis of-lactam ring by catalyzing the hydrolysis of ββ-- lactum ringlactum ring, which results in the loss of antibacterial property of antibiotics. Thus, which results in the loss of antibacterial property of antibiotics. Thus micro-organisms exhibit resistance.micro-organisms exhibit resistance.  ββ-lactamase inhibitors are-lactamase inhibitors are ββ-lactam structures that have negligible antibacterial-lactam structures that have negligible antibacterial activity but inhibitactivity but inhibit ββ-lactamases-lactamases..  They can be administered along with penicillinsThey can be administered along with penicillins to protect them fromto protect them from ββ-lactamases-lactamases and broaden(increase) their spectrum of activityand broaden(increase) their spectrum of activity..  ββ-lactamase inhibitors such as-lactamase inhibitors such as Clavulanic acid, Sulbactam, Tazobactum act asClavulanic acid, Sulbactam, Tazobactum act as suicide substrates forsuicide substrates for ββ-lactamase enzymes.-lactamase enzymes.  Suicide substrates are agents which are converted to highly reactive species whenSuicide substrates are agents which are converted to highly reactive species when they ungergo an enzyme-catalyzed reaction. They formthey ungergo an enzyme-catalyzed reaction. They form covalent bonds to thecovalent bonds to the enzyme and inhibit irreversiblyenzyme and inhibit irreversibly..
  48. 48. The agents Clavalunic acid, sulbactam and tazobactam have also been developed as β-lactamase inhibitors. Sulbactum + ampicillin = unasyn. Amoxycillin + Clavulanic acid = Clavulin Augmention Ticarcillin + Clavulanic acid = Timentin Piperacillin + Tazobactam = Tazocin (or) zosyn Allow the “real” drug to get through to bind to the PBP’s Regain gram negative spectrum of activity otherwise lost due
  49. 49.  Clavulanic acid:Clavulanic acid: clavalunic acid was isolated from streptomyces clavuligerus by Bechams inclavalunic acid was isolated from streptomyces clavuligerus by Bechams in 1976.1976. It has weak and unimportant antibiotic activity, but it is powerful andIt has weak and unimportant antibiotic activity, but it is powerful and irreversible inhibitor of most β-lactamases and as such it is now usedirreversible inhibitor of most β-lactamases and as such it is now used in combination with penicillins such as amoxicillinin combination with penicillins such as amoxicillin( Augmentin)( Augmentin)  The structure of clavulanic acid was the first example of a naturally occuringThe structure of clavulanic acid was the first example of a naturally occuring β-lactam ring that was not fused to a sulfur-containing ring.β-lactam ring that was not fused to a sulfur-containing ring.  It is fused instead to an oxazolidine ring structure.It is fused instead to an oxazolidine ring structure. ESSENTIAL REQUIREMENTS FORESSENTIAL REQUIREMENTS FOR ββ-lactamase inhibition are:-lactamase inhibition are:  StrainedStrained ββ-lactam ring.-lactam ring.  Enol ether.Enol ether.  The double bond of the enol ether has the Z configuration(Activity is reducedThe double bond of the enol ether has the Z configuration(Activity is reduced but not eliminated if the double bond is E)but not eliminated if the double bond is E)  No substitution at C-6No substitution at C-6  R- Stereochemistry at positions 2 and 5.R- Stereochemistry at positions 2 and 5.  Carboxylic acid group.Carboxylic acid group.
  50. 50. Resistance to the B-lactam Antibiotics 1. Differences in PBP’s - Decreased affinity of the PBP for the binding of the Abx - Increased production / concentration of PBP’s produced 2. B-lactamase production - Spectrum of activity of various B-lactamases - Concentration of B-lactamases produced 3. Decreased ability to penetrate to the PBP target - Primarily due to the LPS layer of gram –ve bacteria
  51. 51.  Penicillin’s may be used to treat infections such as urinary tract infections.Penicillin’s may be used to treat infections such as urinary tract infections.  Septicaemia, meningitis, intra-abdominal infection, respiratory infections, ear,Septicaemia, meningitis, intra-abdominal infection, respiratory infections, ear, nose and throat infections.nose and throat infections.  Skin and Soft tissue infections. Examples of infectious micro organisms (bacteria)Skin and Soft tissue infections. Examples of infectious micro organisms (bacteria) that may respond to penicillin therapy includethat may respond to penicillin therapy include  * Streptococcal infections* Streptococcal infections * Pneumococcal infections* Pneumococcal infections * Meningococcal infections* Meningococcal infections * Gonorrhoea* Gonorrhoea * Syphilis* Syphilis * Diphtheria* Diphtheria * Tetanus and gas gangrene* Tetanus and gas gangrene DRUG OF CHOICE for *Anaerobic anthrax*DRUG OF CHOICE for *Anaerobic anthrax* * Actinomycosis* Actinomycosis * Trench mouth* Trench mouth * Rat bite fever* Rat bite fever * Listeria monocytogenes* Listeria monocytogenes * Pasteurella multocida* Pasteurella multocida
  52. 52.  Penicillins are available only with a prescription. Penicillin’s are useful againstPenicillins are available only with a prescription. Penicillin’s are useful against infections in many parts of the body, including the mouth and throat, skin andinfections in many parts of the body, including the mouth and throat, skin and soft tissue, tonsils, heart, lungs, and ears. For example, dentists often prescribesoft tissue, tonsils, heart, lungs, and ears. For example, dentists often prescribe penicillin to prevent infections after dental surgery.penicillin to prevent infections after dental surgery.  Biosynthetic penicillins are important in chemotherapy. They are used inBiosynthetic penicillins are important in chemotherapy. They are used in treating streptococcal sore throat, tonsillitis, pneumococcal pneumonia,treating streptococcal sore throat, tonsillitis, pneumococcal pneumonia, endocardities caused by some streptococci, syphilis, gonorrhoea, meningococcalendocardities caused by some streptococci, syphilis, gonorrhoea, meningococcal infections and infections that are caused by some anaerobic organisms.infections and infections that are caused by some anaerobic organisms.  The drug Augmentin, for example, contains a combination ofThe drug Augmentin, for example, contains a combination of amoxicillin(500mg) and a β-lactamase inhibitor, clavulanic acid (125mg)amoxicillin(500mg) and a β-lactamase inhibitor, clavulanic acid (125mg) usedused in the treatment of Feverish patients with neutropenia from cancerin the treatment of Feverish patients with neutropenia from cancer chemotherapy.chemotherapy. It is also useful in treating the sinusitis. Animal/human biteIt is also useful in treating the sinusitis. Animal/human bite wounds, otitis media in children.wounds, otitis media in children.  There are several types of penicillins, each used to treat different kinds ofThere are several types of penicillins, each used to treat different kinds of infections.infections.  These drugs will not work for, flu, and other infections caused by viruses.These drugs will not work for, flu, and other infections caused by viruses.
  53. 53.  Adverse/toxic effects of penicillins:-  Although most penicillins are safe for the majority of people, some people may experience side effects. Once an individual is allergic to one penicillin, he or she is most likely allergic to all of the penicillins.  The most serious allergic reaction is anaphylaxis that can be fatal which is not treated properly.  a severe allergic reaction that can cause skin rash, itching, difficulty breathing,a severe allergic reaction that can cause skin rash, itching, difficulty breathing, shock, and unconsciousness.shock, and unconsciousness.  An early sign of anaphylaxis is a feeling of warmth and flushing. If any ofAn early sign of anaphylaxis is a feeling of warmth and flushing. If any of these occurs, the medicine should be stopped and emergency help soughtthese occurs, the medicine should be stopped and emergency help sought immediately.immediately.  Anaphylactic shock occurs more frequently after parenteral administration butAnaphylactic shock occurs more frequently after parenteral administration but can occur with oral use.can occur with oral use.
  54. 54. After 7 days this allergy occurred her after penicillin has been taken for throat Infection. That is Late hypersensityvity.
  55. 55. Nausea Dizziness Headache In((inflammation of blood vessels) Skinrashes fever Bronchospasm (Constriction of the Airways of the Lungs) Angioodema(swelling of lips, face and tongue)
  56. 56. Less common side effects of penicillins are  1. Nausea 2. Diziness 3. Head ache 4. skin rashes 5. Bronchospasm 6. vasculitis 7. inflammation of blood vessels 8. constriction of the airways of the lungs 9. fever 10. Angioedema or swelling of lips, face and tongue.  Other most common side effects are mild diarrhoea, vomiting, headache, vaginal itching and discharge, sore mouth or tongue, or white patches in the mouth or on the tongue. These problems usually go away as the body adjusts to the drug and do not require medical treatment unless they continue or they are bothersome.  Occasionally, certain types of penicillin may cause the tongue to darken or discolour. This condition is temporary and will go away when the medicine is stopped.  Effect on GITEffect on GIT: Broad spectrum penicillins like Ampicillin, when administered: Broad spectrum penicillins like Ampicillin, when administered orally, alters the bacterial flora in the intestines and leads to GIT disturbances likeorally, alters the bacterial flora in the intestines and leads to GIT disturbances like diarrhoea .diarrhoea .  On rare occasions some types of penicillin may cause severe abdominal or stomachOn rare occasions some types of penicillin may cause severe abdominal or stomach cramps, pain, or bloating or severe or bloody diarrhoea. Other rare side effectscramps, pain, or bloating or severe or bloody diarrhoea. Other rare side effects include fever, increased thirst, severe nausea or vomiting, unusual tiredness orinclude fever, increased thirst, severe nausea or vomiting, unusual tiredness or weakness, weight loss, seizures, or unusual bleeding or bruising .weakness, weight loss, seizures, or unusual bleeding or bruising .  Over dosage/Acute ToxicityOver dosage/Acute Toxicity - Acute oral penicillin overdoses are unlikely to- Acute oral penicillin overdoses are unlikely to cause significant problems other than GI distress, but other effects are possible .Incause significant problems other than GI distress, but other effects are possible .In humans, very high dosages of parenteral penicillin’s, especially in patients withhumans, very high dosages of parenteral penicillin’s, especially in patients with renal disease, have induced CNS effects.renal disease, have induced CNS effects.
  57. 57. Hypersensitivity or allergic reactions :  Hypersensitivity to penicillin’s is caused by the degradation products of penicillins. The degradation products of penicilloic acid, sodium benzyl penicilloate (of β-lactum ring) binds ie combines to serum proteins initiating an IgE and initiates the IgE mediated inflammatory reactions  It occurs in about 5-8% of the patients and according to estimation, 300-500 people have been dieing each year form penicillin induced anaphylaxis.  Hypersensitivity reactions are classified into  A) Immediate Hypersensitivity  b) Accelerated Hypersensitivity  C) Late Hypersensitivity
  58. 58.  A)A) Immediate hypersensitivityImmediate hypersensitivity:: -- This occursThis occurs within 20 minwithin 20 min. of parenteral. of parenteral administration of penicillin and is characterized by the prurities, skinadministration of penicillin and is characterized by the prurities, skin rashes, wheezing, rhinitis, sneezing.rashes, wheezing, rhinitis, sneezing.  These reactions are transformed in to anaphylaxis (extreme from ofThese reactions are transformed in to anaphylaxis (extreme from of immediate hypersensitivity reaction) that it is characterised by hypotensiveimmediate hypersensitivity reaction) that it is characterised by hypotensive shock, angioneurotic oedema, choking, loss of consciousness and finallyshock, angioneurotic oedema, choking, loss of consciousness and finally death.death.  Serious anaphylaxis reactions require immediate emergency treatment withSerious anaphylaxis reactions require immediate emergency treatment with ephedrine, oxygen, IV steroids and airway management, includingephedrine, oxygen, IV steroids and airway management, including intubations should also be administered as indicated.intubations should also be administered as indicated.  B)B) Accelerated HypersensitivityAccelerated Hypersensitivity:: - It occurs- It occurs within few hourswithin few hours afterafter penicillin has been administered. Accelerated hypersensitivity reactions arepenicillin has been administered. Accelerated hypersensitivity reactions are characterized by skin rashes, fever, urticaria, angioneurotic oedema. Deathcharacterized by skin rashes, fever, urticaria, angioneurotic oedema. Death is a rare consequence.is a rare consequence.  c)c) Late HypersensitivityLate Hypersensitivity:: It occursIt occurs after 72 hoursafter 72 hours after penicillin hasafter penicillin has been administered. This reaction is mediated by IgE and IgM antibodiesbeen administered. This reaction is mediated by IgE and IgM antibodies and manifested byand manifested by utricaria, skin rashes similar to measles, localutricaria, skin rashes similar to measles, local inflammation, serum sickness and coomb’s positive haemolytic anaemiainflammation, serum sickness and coomb’s positive haemolytic anaemia
  59. 59. Penicillin's advantages and disadvantagesPenicillin's advantages and disadvantages  Penicillin's disadvantagesPenicillin's disadvantages::  Acid liability - most of these drugs are destroyed by gastric acid.Acid liability - most of these drugs are destroyed by gastric acid.  Short duration of action - because of this short half-life, the penicillin's must be at shortShort duration of action - because of this short half-life, the penicillin's must be at short intervals, usually every 4 hours.intervals, usually every 4 hours.  Lack of activity against most gram-negative organisms.Lack of activity against most gram-negative organisms.  Drug hypersensitivity - about 10 % of population has allergy.Drug hypersensitivity - about 10 % of population has allergy.  Many patients experience GI upset.Many patients experience GI upset.  Painful if given intramuscularly.Painful if given intramuscularly.  penicillin's advantagespenicillin's advantages::  Bactericidal against sensitive strains.Bactericidal against sensitive strains.  Relatively nontoxic.Relatively nontoxic.  Have excellent tissue penetration.Have excellent tissue penetration.  Efficacious in the treatment of infections.Efficacious in the treatment of infections.  Relatively inexpensive in comparison with other antibiotics.Relatively inexpensive in comparison with other antibiotics.  Newer penicillin's are resistant to stomach acid, such as penicillin v, or have a broaderNewer penicillin's are resistant to stomach acid, such as penicillin v, or have a broader spectrum, such as Ampicillin and Amoxicillin.spectrum, such as Ampicillin and Amoxicillin.
  60. 60. Key pointsKey points  Penicillins have aPenicillins have a bicyclic structurebicyclic structure consisting of aconsisting of a ββ-lactam ring fused to a-lactam ring fused to a Thiazolidine ring.Thiazolidine ring.  The strainedThe strained ββ-lactam ring reacts irreversibly with the transpeptidase enzyme-lactam ring reacts irreversibly with the transpeptidase enzyme responsible for the final cross-linking of the bacterial cell wall.responsible for the final cross-linking of the bacterial cell wall.  Penicillin can be made more resistant to acid conditions by incorporating anPenicillin can be made more resistant to acid conditions by incorporating an electronelectron withdrawing groupwithdrawing group into the acyl side chain.into the acyl side chain.  Stereic shieldStereic shield can be added to penicillins to protect them from bacterialcan be added to penicillins to protect them from bacterial ββ-lactamase-lactamase enzymes.enzymes.  Broad spectrum activityBroad spectrum activity is associated with the presence of anis associated with the presence of an αα-hydrophilic group-hydrophilic group on the acyl side chain of penicillins.on the acyl side chain of penicillins.
  61. 61. Prof. Panchumarthy Ravisankar

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