Antibiotics, characteristics of an antibiotic, Brief historical background of antibiotics, Modern History of antibiotics, Classification of antibiotics, four groups of beta-lactam antibiotics, Classification of Penicillins, Penicillinase resistant Penicillins, Narrow spectrum anti-staphylococcal Penicillins, Amino Penicillins, Nomenclature of Penicillins, Stereochemistry of Penicillins, Hydrolysis of Penicillins, SAR of Penicillins, Mechanism of Penicillins, Beta-lactamase inhibitors, Therapeutic uses of Penicillins, Penicillin advantages, and disadvantages, Hypersensitivity or allergic reactions of Penicillins.

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.
Phone no:9000199106

2. “Antibiotics are defined as chemical substances or compounds
produced by various species of microorganisms such as bacteria
and fungi, which in low concentrations destroy, kill or abolish the
growth of other species of microorganisms.”
Greek words anti = against ; bios = life
Vuillemin defines antibiotics literally meaning “against life”
➢In 1942 Waksman proposed the widely cited definition that “an antibiotic is a
substance produced by microorganisms, which has the capacity of inhibiting the
growth and even of destroying other microorganisms”.
➢ The word antibiotic came from the word antibiosis a term
coined in 1889 by Louis Pasteur's pupil Paul Vuillemin which
means a process by which life could be used to destroy life.
However, by acylating it with various acid derivatives, more than
50,000 semisynthetic penicillins have been made, of which less than 30
are currently used in medicine.
DEFINITION:

3. Requirements for a substance to be considered as an antibiotic
◼
-It should have a wide spectrum of activity with the ability to destroy
or inhibit many different species of pathogenic organisms.
◼ -It should be eliminated completely from the body.
◼ -It should not produce adverse and side effects.
◼ -It should antagonizes the growth or survival of one or more species
of micro- organisms.
◼ -It should be highly effective in low concentrations.
◼ -It should be nonallergenic to the host.
◼ -It should not eliminate the normal flora of the host.
◼ -It should be able to reach the part of the human body where
the infection is occurring.
◼ -It should be inexpensive and easy to produce.
◼ -It should be chemically-stable (have a long shelf-life).
◼ -It is a product of metabolism (although it may be duplicated or even
have been anticipated by chemical synthesis).

4. ◼ History of antibiotics can be described in two segments early history and modern
history.
◼ Most important is the discovery of penicillin by SIR Alexander Fleming.
◼ EARLY HISTORY:
◼ During ancient times:
◼ Long ago before 20th century there was no proper treatment for diseases.
The diseases caused by Mycobacterium tuberculosis, Mycobacterium leprae were not identified
.
◼ Over 2,500 years ago , Chinese used plants and moldy cheese used to treat infected wounds.
◼ As early as 500 to 600 BC, molded curd of soybean was used in Chinese folk medicine to treat
boils and carbuncles.
◼ The ancient Egyptians used honey + lint (soft cotton cloth covering and protecting
wounds)+lard (melted fat of pigs) used as ointment for dressing wounds.
◼ Egyptians have often been found onions in body cavities of mummies. They used onions,
garlic and radish herb therapeutically. Infact they have anti-infective properties.
◼ Greeks and Indians used moulds and other plants to treat infections.
◼ In Greece and Serbia, moldy bread was traditionally used to treat wounds and
infections.
◼ Warm soil was used by Russians to cure infected wounds.
◼ Sumerian doctors gave patients beer soup mixed with turtle shells and snake skins.
◼ Babylonian doctors healed the eyes using a mixture of frog bile and sour milk.
Sri Lankan army used oil cake (sweetmeat) to serve as antibacterial.

5. Modern History
◼ Late 1800’s = Search for antibiotics began with the growing acceptance of the germ theory of
disease(Louis Pasteur was one of the first recognized physicians who observed that bacteria could be
used to kill other bacteria)
◼ 1871 = The surgeon joseph lister found urine contaminated with
mould couldn't kill the bacteria.
◼ 1890’s = German doctors Rudolf emmerich, oscar low made
pyocyanse from microbes. It was the first antibiotic used
in hospitals but the drug did not work.
◼ 1909 =First modern chemotherapeutic agent SALVARSAN for the
treatment of syphilis.(Paul Ehrlich)
◼ 1928 = Scottish bacteriologist Sir Alexander Fleming discovered enzyme
lysozyme and the antibiotic substance penicillin.
◼ 1932 = Gerhard Domagk discovered Prontosil a prodrug.
◼ 1936 = Sulfanilamide the first synthetic sulfonamide in human medicine.
◼ 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.
◼ 1940 =First therapeutic use of penicillin by Floury.
◼ 1944 = Selman waksman made Streptomycin from soil bacteria.
◼ 1948 = Chlortetracycline.
◼ 1957 = Nystatin (fungal infections)
◼ 1970’s = New 4-quinolones(pipemidic acid,oxolinic acid,cinoxacin)
◼ 1980 =Norfloxacin, the first fluoroquinolone.
◼ 1980 =Enroflocacin.
◼ 1998 =Smithkline Beecham patented Amoxicillin/clavulanate potassium tablets
the first sold antibiotic under the trade names of Amoxil and trimox.

6. ◼ CLASSIFICATION: Antibiotics are classified in many ways based on chemical structure, source,its
spectrum of activity and Mechanism of action (MOA).
◼ *Based on the chemical structure:
◼ 1.β-lactam antibiotics: Penicillin's, Cephalosporin's, carbapenems, monobactams.
◼ 2. Aminoglycoside antibiotics: Streptomycin, Neomycin, Kanamycin, Gentamycin, Tobramycin, Amikacin.
◼ 3. Tetracyclines: Tetracycline, Chlortetracycline, Oxytetracycline, Doxycycline, Minocycline,
methacycline, meclocycline.
◼ 4. Macrolide antibiotics: (i.e., large macrolide structure): Erythromycin, Clarithromycin, Azithromycin, Roxithromycin.
◼ 5. Polypeptide antibiotics: Actinomycin, Bacitracin, Colistin, Polymyxin B, tyrothricin
◼ 6. Polyenes: Amphotericin B, Nystatin.
◼ 7. Lincomycin: Clindamycin.
◼ 8. Miscellaneous: Chloramphenicol, Novobiocin, Mupirocin, Fusidic acid.
◼ *Based on the source: They are divided into
◼ Natural antibiotics: Penicillium chrysogenum---- Penicillin.
◼ Bacillus subtilis --------------- Bacitracin.
◼ Bacillus polymyxa ------------- Polymyxin.
◼ Stryptomyces griseus---------- Stryptomycin.
◼ Streptomyces aureofaciens ---Chlortetracyclines
◼ Streptomycers erythreus -------Erythromycin
◼ Streptomyces venezulae------- Chloramphenicol.
◼ Semisynthetic antibiotics: These antibiotics are commercially synthesized by adding chemical
compounds, 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 side
chain.
◼ Ex: Ampicillin, Amoxacillin, Oxacillin, Cloxacillin, Dicloxacillin, Carbenicillin. Methicillin.
◼ *Spectrum Activity:
◼ Broad spectrum: These antibiotics inhibit the growth of a wide range (i.e. More than one species) of
microorganisms. Some antibiotics can inhibit both Gram-positive and Gram-negative bacteria.
◼ EX: Cephalosporins, Chloramphenicol, Tetracyclines.
◼ Narrow spectrum: These antibiotics are effective mainly against a single species of microorganism either
◼ Gram +ve (or) Gram –ve bacteria. EX: - Bacitracin, Nystatin, Penicillin, erythromycin, streptomycin.

7. ◼ Antibiotic activity :Based on their activity against different m.o’s they are divided in to
◼ a. Antibacterial antibiotics: The chemotherapeutic agents which kill or inhibit the growth of bacteria
◼ are called antibacterial antibiotics. (penicillins, cephalosporins, tetracyclines, aminoglycosides)
◼ 1. Bactericidal antibiotics: These drugs kill or irreversibly damage the multiplying bacteria, which decreases their
number.
species. (Kill the bacteria directly) Examples are …..
2. Bacteriostatic antibiotics These drugs arrest the further growth of bacteria and thus inhibit the spread of infection. (stop
the bacteria from growing):
EX: Tetracyclines, Chloramphenicol, Clindamycin, Macrolide antibiotics, sulfonamides, trimethoprim,
nitrofurantoin.
b. Antifungal antibiotics: Griseofulvin, Amphoterisin B, Nystatin.
c . Anthelmintic agents : Ivermectin.
d. Anticancer antibiotics: Bleomycin, Dactinomycin, Doxorubicin.
Based on Mechanism of action (MOA) :
Cell wall synthesis inhibitors: Penicillins, Cephalosporins, Carbapenems, Aztreonam, bacitracin,
cycloserine, vancomycin.
Alteration of cell membrane integrity: Amphotericin B, Bacitracin, Colistin, Nystation, Polymyxin B
Protein synthesis inhibitors: Aminoglycosides, Macrolides, Tetracyclines. Chloramphenicol, erythromycin,
clindamycin, Linezolid, mucopurin, Fusidic acid.

8. Inhibition of DNA synthesis:
a. Inhibition of DNA gyrase: Fluoroquinolones.
b. Interfering DNA function: Acyclovir, zidovudine.
c. Inhibition of RNA polymerase: Rifampin (inhibits bacterial RNA polymerase
Foscarnet ( inhibits viral RNA polymerase)
d. Inhibits folate synthesis: Sulphonamides, Trimethoprim.
e. Alteration of base pairing Properties of the template: Acriflavine.

9. ➢In carbapenems, the beta-lactam ring is also
joined to a five-membered ring, although it is
carbocyclic.
➢Monobactams have a monocyclic beta-lactam
structure, and the side sulfo-group is joined to a
nitrogen atom.
Four groups Beta-lactam antibiotics

10. Biological sources of penicillin
◼ The first naturally occurring benzyl penicillin (penicillin G is also
referred to as gold standard penicillin ) was obtained by the
fermentation of fungus Penicillium notatum.
◼ At present it is obtained from a highly yielding strain called
Penicillium chrysogenum and other penicillum species.
◼ 30 different biosynthetic penicillin's have been isolated from various
strains of Penicillium notatium and Penicillum chrysogenum.

11. Classes of Penicillins
1. Natural Penicillins (Fermentation derived penicillins) (Moderate spectrum)
Penicillin G (given IV), (acid-labile), Penicillin V (given orally) (and phenoxy methyl penicillin (acid-
stable) narrow spectrum natural penicillinase sensitive moderate weight penicillins. They can kill gram-ve
and a few gram–ve. (kill gram +ve cocci, gram + bacilli and a few gram –ve cocci but not gram –ve
bacilli) penicillin V protects the molecule from acid attack but not penicillinase. It can be used orally.
2. Semi-synthetic penicillins
a. Acid-resistant penicillins: b. Semisynthetic Pencillinase-resistant parenteral penicillins (made very
very narrow spectrum heavy or bulky (obese) action lost on the gram –ve. Anti-staphylococcal penicillins
especially attack the staphylococcus they produce secrete penicillinase or beta-lactamase ): Methicillin not
been used nowadays, and Nafcillin produces neutropenia
Semisynthetic Penicillinase Resistant oral penicillins: Oxacillin, Cloxacillin,
Dicloxacillin, Flucloxacillin.
Extended-spectrum: (we want sth. Smart penicillins sneak through both gram +ve and gram –ve). wider
spectrum work or effective not only on gram +ve but work effectively on the gram –Ve also ).
Amino penicillins ( Semisynthetic penicillinase-sensitive broad-spectrum oral penicillins) : Ampicillin,
Amoxicillin. (model or smart penicillins, spectrum (because they are too much smart and vulnerable to
attack we send them with bodyguards sulbactam and clavulanic acid)
Semisynthetic penicillinase-sensitive, broad-spectrum parenteral penicillins:
Antipseudomonal Penicillins ( Acid labile)
Then we made it super smart which type of bug especially? pseudomonas. There is an organism that
produces green pus. Pseudomonas aeruginosa protects wonderfully. It has very very narrow or few porins.
Model penicillins fail. When a model fails who will succeed super smart or model penicillins
(antipseudomonal penicillins or James bond penicillins)?
Carboxy penicillins: Carbenicillin, Carbenicillin phenyl, Carbenicillin indanyl. Ticarcillin
Ureido penicillins (supermodel penicillins) are at high risk of attack by penicillinases Ex: Azlocillin,
Mezlocillin, and Piperacillin( more potent means destroy the bacteria even in low doses).

12. STRUCTURE
OF PENICILLINS

13. Penicillin G (Benzylpenicillin)
◼ Penicillin G is also referred to as gold standard penicillin. Penicillin G is not acid resistant it is acid sensitive.
◼ 3 reasons for the acid sensitivity of penicillin G.
◼ 1. Ring strain. ( 4 membered beta-lactam ring + 5 membered thiazolidine ring) As a result, penicillins suffer large
angle and torsional strains. Acid-catalyzed ring opening relieves these strains by breaking open the more highly β –
lactam ring.
◼ 2. Highly reactive corbonyl group. The resonance stabilization is impossible for the β –lactam ring because of the
increase in angle strain that would result in having a double bond within β –lactam ring. So the angle of the β –
lactam ring is constrained to 900. 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.
◼ Influence of the acyl side chain: Acyl group opens up the lactam ring. So Penicillin G has a self-destruct mechanism
built into its structure.
Benzylpenicillin is broken down by stomach acid
and destroyed by staphylococcus penicillinase.
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.

14. N
S
COOH
H
CH3
CH3
H
H
O
HN
C
H2C
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

16. 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 -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.

17. The acidic stability of the ampicillin also attributes to the electron-withdrawing character of the primary
amino group which prevents the hydrolysis of the β-lactam bond. It is susceptible to degradation by β-
lactamase enzymes. Hence it is given in Combination with inhibitors like sulbactam.
➢Hydrophobic groups on the side chain ( Ex: penicillin G) favor activity against Gram-positive bacteria
➢Hydrophilic groups on the side chain have increased 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 –stands for Haemophilus influenza.
E – Escherichia Coli.
L – Listeria monocytogenes.
P- Proteus.
S – Salmonella Typhi.
Amino Penicillins ( Ampicillin, Amoxicillin )
AMPICILLIN
N
S CH3
CH3
COOH
O
HN
O
C
H
H H
NH2
H
(2S,5R,6R)-6-{[(2R)-2-Amino-2-phenylacetyl]amino}-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid

18. Amoxicillin (Amoxil) (p-hydroxy Ampicillin)
Amoxicillin is very similar in structure to 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 the dipolar nature of the molecule
It has both free carboxylic acid and amino functions.
This problem can be solved by using a prodrug Pivampicillin, talampicillin, bacampicillin is prodrugs of ampicillin.
acetoxymethyl esters are used to mask the -COOH groups.
Its spectrum of activity is increased when administered with clavulanic 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. An extra phenol group is present in amoxicillin.
If you compare it with ampicillin, amoxicillin is better absorbed
through the gut wall.
2S,5R,6R)-6-[[(2R)-2-amino-2-(4-hydroxyphenyl)acetyl]amino]-3,3-dimethyl-
7-oxo-4-thia-1-azabicyclo [3.2.0]heptane-2-carboxylic acid
Uses:
Bronchitis
Pneumonia
Typhoid
Enteric fever
Gonorrhoea
Urinary tract infections.
N
S CH3
CH3
COOH
O
HN
O
C
H
H H
NH2
H
HO

19. Ampicillin synthesis:
A method of directly acylating 6-APA with phenylglycine chloride hydrochloride
Ampicillin
Amoxicillin synthesis:
The direct reaction of 2-(4-hydroxyphenyl) glycine chloride hydrochloride with
trimethylsylil ester of 6-APA
Amoxicillin

21. Nomenclature of Penicillins
Nomenclature 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
3
4
5
6
7
Bicyclic ring system
6-acylamino-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
5
6
7
4-thia-1-azabicyclo [3.2.0] heptane
1 2
2
3
4
5
6
7
1
2
3
4
5
6
7

22. 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 5- 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
5
6
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 ring Modified Derivatives.

24. Reactions: Hydrolysis of penicillins by hot and cold dilute mineral acid

25. 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 inactivates the molecule.

31. ◼ Penicillin’s may be used to treat infections such as urinary tract infections.
◼ Septicaemia, meningitis, intra-abdominal infection, respiratory infections, ear, nose
and throat infections.
◼ Skin and Soft tissue infections. Examples of infectious micro organisms (bacteria)
that may respond to penicillin therapy include
◼ * Streptococcal infections
* Pneumococcal infections
* Meningococcal infections
* Gonorrhoea
* Syphilis
* Diphtheria
* Tetanus and gas gangrene
DRUG OF CHOICE for *Anaerobic anthrax*
* Actinomycosis
* Trench mouth
* Rat bite fever
* Listeria monocytogenes
* Pasteurella multocida

32. Nausea
Headache
Vomiting
Giddiness
Diarrhoea
Angioedema
Bronchospasm
Skin rashes
COMMON SIDE EFFECTS OF PENICILLINS

33. ▪ A) Immediate hypersensitivity: - This occurs within 20 min. of parenteral
administration of penicillin and is characterized by the prurities, skin rashes,
wheezing, rhinitis, sneezing.
▪ These reactions are transformed in to anaphylaxis (extreme from of
immediate hypersensitivity reaction) that it is characterised by hypotensive
shock, angioneurotic oedema, choking, loss of consciousness and finally
death.
▪ Serious anaphylaxis reactions require immediate emergency treatment with
ephedrine, oxygen, IV steroids and airway management, including
intubations should also be administered as indicated.
◼ B) Accelerated Hypersensitivity: - It occurs within few hours after
penicillin has been administered. Accelerated hypersensitivity reactions are
characterized by skin rashes, fever, urticaria, angioneurotic oedema. Death
is a rare consequence.
◼ c) Late Hypersensitivity: It occurs after 72 hours after penicillin has
been administered. This reaction is mediated by IgE and IgM antibodies
and manifested by utricaria, skin rashes similar to measles, local
inflammation, serum sickness and coomb’s positive haemolytic anaemia
Hypersensitivity or allergic reactions
:

34. Penicillin's advantages and disadvantages
◼ Penicillin's disadvantages:
◼ 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 short
intervals, usually every 4 hours.
◼ Lack of activity against most gram-negative organisms.
◼ Drug hypersensitivity - about 10 % of population has allergy.
◼ Many patients experience GI upset.
◼ Painful if given intramuscularly.
◼
penicillin's advantages:
◼ Bactericidal against sensitive strains.
◼ Relatively nontoxic.
◼ Have excellent tissue penetration.
◼ Efficacious in the treatment of infections.
◼ Relatively inexpensive in comparison with other antibiotics.
◼ Newer penicillin's are resistant to stomach acid, such as penicillin v, or have a broader
spectrum, such as Ampicillin and Amoxicillin.

35. Prof. Panchumarthy Ravisankar