Guided & Checked By : Shreyas Bhatt sir Shreya M. Modi MSc Sem- III Roll no.- 11
Antibiotics are chemical molecules or compounds that specifically targets and kill cells. Not only antibacterial, but also antifungal, antiviral and also antineoplastic compounds are also classified as antibiotics. Antibacterial action generally follows some of the mechanisms such as inhibition or regulation of enzymes involved in the synthesis of cell wall, nucleic acid synthesis and repair, or protein biosynthesis. Antibiotics target the cell functioning of rapidly dividing cells.
1. The target of an antibiotic can be present only in bacteria but not in the eukaryotic host. 2. The target in bacteria is different from the homologous target in the eukaryotic host. Modern genomics provide a great tool foridentifying targets of new selective antibiotics
Natural antibiotics are weapons that bacteria or fungi use to compete with other microorganisms. Selectivity is not a ‘natural’ feature of antibiotics. Most of clinically-useful antibiotics are fortuitously selective antibacterials.Many antibiotics are omni-potent and inhibit growth of a wide variety of organisms. Such antibiotics can bedeveloped into selective drugs through modification of their chemical structures.
Bacteriostatic drugs make Bactericidal drugs killbacteria dormant, but do not bacteria (e.g. kill them. ciprofloxacin) Most bacterial cells resumegrowth after removal of the antibiotic (e.g. chloramphenicol)
Antibiotics with a bactericidal mode of action are preferred, especially for treatment ofimmunocompromised patients. The mode (static vs. cidal) of antibiotic action may differ fordifferent pathogens and may depend on the drug concentration. The basis of bactericidal versus bacteriostaticeffects is poorly understood but maybe related to the accumulation of reactive oxygen radicals in the bacterial cells upon treatment with bactericidal drugs.
sulfonamides 1920 -lactams 1942 aminoglycosides 1947 tetracycline 1949 macrolides 1952 glycopeptides 1958 streptogramins 1962 lincosamides No Golden era in antibiotic discovery principally new antibioticsGrowing resistance linezolid 2000 daptomycin 2003
Some of the antibacterial compounds interfere with the cell wall synthesis by weakening the peptidoglycan structures in bacterial cell wall, by this integrity of bacterial cell wall structure weakens and eventually disrupts. Mammalian cells only have plasma membrane so these antibiotics specifically target only bacterial cells. That is these antibiotics do not induce any negative effect on the host mammalian cells.
Antibacterial compound β-lactam can be used against both Gram-positive and Gram-negative bacterial cells. Vancomycin another antibacterial compound also prevents cell wall biosynthesis in bacterial cells by interfering with transglycosylases enzyme activity. But this compound can be used effectively against Gram-positive bacteria, as it is unable to penetrate the outer cytoplasmic membrane of Gram-positive bacteria.
Name Producer Chemical nature Site of action organismPenicillin P.Notatum Β lactum Transpeptidase P.Crysogenum Antibiotic ReactionCephalosporine Cephalosporium Β lactum Transpeptidase aeremonium Antibiotic ReactionCycloserine Streptomyces Analogue of Inhibit formation spp. alanine of Park’s nucleotideBacitracin B.Subtilis Peptide Phosphatase reaction in lipid cycleVancomycin Str.orientatis Glycopeptide Polymerization step
FosfomycinThe first stage BacitracinThe second stageThe third ß-lactam stage antibiotics.
Beta-lactam antibiotics Penicilins Cephalosporins Carbapenems Monobactams All β-lactam antibiotic agents contain a β-lactam nucleus in its molecular structure.Core structure of penicillins (1) and cephalosporins (2).Beta-lactam ring in red.
All beta-lactams: are bacteriocidal. have the same mechanism of antibacterial action. have no activity against MRSA and atypical bacteria (Legionella spp., Mycoplasma spp., Chlamidia spp.). have the allergic cross-reaction. have the same modes of bacterial resistance.
Penicillin-binding proteins (PBPs), enzymesthat catalyze the last steps of peptidoglycan synthesis (cross-linking). β-Lactam antibiotics are analogues of D- alanyl-D-alanine amino acid residues irreversible binding to the active site of penecillin-binding proteins (PBPs)
Inhibition of the PBPs prevents the final crosslinking of the nascent peptidoglycan layerdisrupting bacterial cell (bactericidal effect)
Generation Example Clinical useNatural penicillins Penicillin G Syphilis, rheumatic fever meningitis, tonsillitis, scarlet fever, endocarditisAntistaphylococcal Methicillin Mild and moderatepenicillins staphylococcal infectionsExtended-spectrum Ampicillin Noncomplicatedpenicillins Amoxicillin community-acquired infections (lower and upper respiratory tract infections, UTIs, skin and soft tissues)Antipseudomonal Carbenicillin P.aeruginosa infectionspenicillins
Some antibiotics inhibit the action of enzyme RNA polymerase, hence interfere with RNA (ribonucleic acid) synthesis in the cells. Antibiotics such as asdoxorubicin andactinomycin D interfere with RNA biosynthesis in both bacterial cells as well as in mammalian cells. These compounds are used in treating rapidly growing tumor cells in cancer patients. Some of the examples are Doxorubicin hydrochloride, Levofloxacin, Irinotecan hydrochloride, Rifampcin
Penicillin G Still useful for a number of diseases (e.g. meningitis, syphilis) Cloxacillin For MSSA infections Ampicillin, amoxicillin Active vs. Gram-positive (not MSSA), Gram- negative organisms Augmentin, Unasyn Broad spectrum, covers Gram-positive, Gram- negative and anaerobes Piperacillin, Tazocin, Timentin Are active vs. Pseudomonas
Generation Example SpectrumFirst Cefazolin Most active against gram-positiveGeneration bacteria (staphylococci). Have no activity against gram-negative bacteria.Second Cefuroxim Enhanced activity against gram-Generation positive and some gram-negative bacteria.Third Cefotaxime Broad-spectrum (gram-positive andGeneration gram-negative). Resistant to most type of beta-lactamases.Fourth Cefepime Most active against gram-negativeGeneration bacteria. Very active against P.aeruginosa. Resistant to beta- lactamases. Have little gram-positive activity.
Imipenem Broad spectrum, covers Gram-positive, Gram- negative (including ESBL-producing strains), Pseudomonas and anaerobes Meropenem Less seizure-inducing potential, can be used to treat CNS infections Ertapenem Lacks activity vs. Acinetobacter and Pseudomonas Has limited activity against penicillin-resistant pneumococci
Is not absorbed from the gut. IV administration. Excreted unchanged by the kidneys.
Forms a complex with the C-terminal D-alanine of peptidoglycan precursorsPrevents the following addition of new units to the peptidoglycan Inhibition of peptidoglycan synthesis Bactericidal effect
Do not penetrates the membrane of gram-negative organisms. Gram positive organisms only Staphylococcus spp. including Methicillin- resistant Staphylococcus aureus (MRSA) Streptococcus spp. Enterococcus faecalis and E. faecium Clostridium difficile and other Clostridia (cause pseudomembranous colitis)
Serious, life-threatening gram-positive infections MRSA infections Pseudomembranous colitis caused by Clostridium difficile (oral administration of vancomycin)
Nephrotoxity: mostly in combinations with aminoglycosides Ototoxicity Red man syndrome (or red neck syndrome): within 4–10 minutes after the start of infusion flushing and an erythematous rash at the face, neck and upper body. is due to non-specific mast cell degranulation. It is not allergic reaction.
Ciprofloxacin Active vs. MSSA, Gram-negative and Pseudomonas Levofloxacin Has activity vs. Streptococcus pneumoniae, but slightly less active towards Pseudomonas compared to ciprofloxacin Moxifloxacin Has activity vs. anaerobes but less active towards Pseudomonas
Active vs. some Gram-positive and Gram-negative organisms Gentamicin Active vs. Pseudomonas Tobramycin More active vs. Pseudomonas than gentamicin Shows less activity against certain other Gram-negative bacteria Amikacin More stable to enzymes, used in severe infections by gentamicin-resistant organisms Streptomycin Used for tuberculosis
Erythromycin Active vs. Gram-positive organisms, atypicals GI side effects Clarithromycin Slightly greater activity than erythromycin Azithromycin Slightly less active than erythromycin vs. Gram- positive but enhanced activity vs. some Gram- negative organisms
Drug of choice in infections caused by Chlamydia, Rickettsia, Brucella and Lyme disease Value has decreased due to increasing bacterial resistance Tetracycline Role in Helicobacter pylori eradication (less frequently used than other antibiotics) Doxycycline Once daily Minocycline Broader spectrum
Clindamycin Vs. Gram-positive cocci and anaerobes Metronidazole Vs. anaerobes Preferred therapy in antibiotic associated diarrhoea (Clostridium difficile) than oral vancomycin, although unlicenced Vancomycin, teicoplanin For Gram-positive organisms (including MRSA)
Cotrimoxazole Role in uncomplicated UTI, UTI prophylaxis, acute exacerbations of chronic bronchitis Pneumocystis carinii (now jiroveci) infections Nitrofurantoin For UTI, prophylaxis vs. UTI Fusidic acid, rifampin For penicillin-resistant staphylococci Not for monotherapy due to risk of emergence of resistance
Inhibition of protein synthesis Structure of prokaryotic ribosome acts as target for many antimicrobials of this class Differences in prokaryotic and eukaryotic ribosomes responsible for selective toxicity Drugs of this class include Aminoglycosides Tetracyclins Macrolids Chloramphenicol Lincosamides Oxazolidinones Streptogramins
RNA, which participate in the protein biosynthesis. DNA, which carries the entire genetic information for the characters to be expressed by the organisms, by acting as hereditary material.
Certain antibiotics are able to bind with the key enzyme involved in RNA synthesis like- RNA polymerese. Binding of antibiotics to this enzyme interferes with the functioning of this enzyme and prevent RNA synthesis.
Certain other antibiotics bind with GC pair of DNA and prevent unfolding of DNA, required for transcription. thus, they inhibit RNA synthesis. E.g.- Mitomycin C Actinomycin D
Antibiotic Mode of actionActinomycin Binds to GC pair of DNA and interferes withD transcription And replication process.Mitomycin C Binds to GC pair of DNA and interferes with transcription And replication process.Rifampicin Binds with β- subunit of bacterial RNA polymerese and Interferes with transcriptional process.Rifamycin Binds with β- subunit of bacterial RNA polymerese and Interferes with transcriptional process.Griseofulvin Binds to DNA polymereseAnthramycin Binds to DNA and damage its structure and
Protein synthesis is a multi-step process. Majority of antibiotics inhibit the process s that occurs in the 30S 0r 50S subunit of 70S bacterial ribosome, this in turn inhibits the protein biosynthesis. Most of the antibiotics inhibits the formation of 30S initiation complex or altogether inhibits the formation of 70S ribosome by the 30S and 50S ribosome subunits or they inhibit assembling of amino acids into a polypeptide chain.
Tetracyclines, includingdoxycycline, block protein synthesis by preventing the binding of aminoacyl- tRNA in 30S ribosome subunit. These compounds block protein synthesis in both prokaryotic and eukaryotic system. Streptomycin interferes with the formation of 30S initiation complex hence inhibits the protein biosynthesis. Erythromycin interferes with the assembly of 50S subunit of ribosome hence inhibit the protein synthesis. Antibiotics lincomycin and clindamycin inhibits enzyme peptidyl transferase, hence prevent the protein synthesis.
Whereas antibiotic puramycin does not inhibits the enzymatic process, but they act as an analoge of 3-terminal end of aminoacyl-tRNA, hence disrupts protein synthesis and causes premature polypeptide chain termination. In other words this antibiotic produces non functional proteins in the cell. Some of the examples for this category of antibiotics are Doxocycline hyclate, Erythromycin, Hygromycin B, Kanamycin disulfate salt and much more.
Name Chemical nature Target site of actionPuromycin Structural analogue Compete with binding of tRNA aminoacyl tRNA at a side on ribosome.Streptomycin Aminoglycoside Binds to 30s ribosomal subunit and cause misreading of codons.Tetracycline Naphthalene ring Binds to 30s ribosomal subunit structure and prevent binding of aminoacyl tRNA to ribosomeChloramphenicol Nitrobenzene Binds to 50s ribosomal subunit Ring and interferes with peptide bond formation.Erythromycin Macrolide ring Binds to 50s ribosomal subunit and interferes with peptide bond formation as well as block translocation step.
Good news A few novel antibiotics have shown promising results / are undergoing clinical studies Bad news As immunosuppressive diseases and use of immunosuppressive agents become more prevalent, opportunistic infections becomes more common, esp. by organisms rarely encountered previously Diseases: e.g. HIV, leukemia Drugs: e.g. in solid organ transplants, bone marrow transplants, rheumatoid disorders Development of bacterial resistance to antibiotics is much faster than research and development of new antibiotics
Antibiotics inhibits the growth of infectiousagents such as bacteria, virus, fungus or othertypes of microorganisms by inhibiting cell wallformation or nucleic acid synthesis or proteinsynthesis.