1.

BETA-LACTAMS Penicillin Type s Natural & Synthetic Binds to enzymes that cross-link peptidoglycansubunits An enzyme called transpeptidase(type of penicillin binding protein) forms the covalent bond between peptide side chains, with release of a terminal D-alanine-Penicillin binds and inhibits this enzyme As the cell wall continues to be formed, the lack of covalent bonds between the peptide side chains eventually results in cell lysis; breakage 2. 1. Cephalosporin

CELL WALL SYNTHESIS INHIBITORS OTHER Cycloserine Bacitracin

GLYCOPEPTIDASE Eg: Vancomycin

Blocking the transpeptidationreaction (forming the peptide crosslinks) By binding to the D-alanylD-alanineportion of the p entapeptidesidechain. This prevents formation of the covalent crosslinksbetween adjacent glycanchains. Similar to betalactamexcept beta lactamdrugs bind to the transpeptidaseenzyme itself Blocking the transgylcosylationreaction (elongating the glycanchains) large molecules that bind to cell wall precursors acts as a stericimpediment Result: Leads to structurally weakened cell wall until the cell lyses only active against G +veorganisms too large to cross G vecell wall

Mode of actions

Blocks synthesis of peptidoglycanprecursors by: inhibiting the conversion of L-alanineto D-alanine preventing the formation of the D-alanyl-Dalaninerequired for peptide side chain formation

Prevents regeneration of carrier molecule required for peptidoglycansynthesis by Inhibiting the enzyme pyrophosphatasethat removes the terminal phosphate from bactoprenolpyrophosphate (carrier molecule). Without removal of the terminal phosphate, bactoprenolcannot be used again to transport cell-wall precursors through the cell membrane

Only effective against growingbacteria no effect on stationary phase cells Not effective against species without cell walls (mycoplasma) with impenetrable cell walls (mycobacteria) That live as intracellular pathogens (Chlamydia) Beware penicillin allergy Least toxic of antibiotics From rash (25%) to anaphylactic shock (0.04% of cases)

Improved activity against Gram-verods Broad-spectrum For patients allergic to penicillin Although 10% of patients allergic to penicillin also allergic to cephalosporin Has it own side effects: thrombophlebitis, GIT disturbance

side effects: confusion, coma, liver damage Second-line drug for TB treatment

Topical use only (can cause kidney & liver damage) Effective against G +ve(Staphylococciand Streptococci)

Properties

Aminoglycosides bind to 30S ribosome and can Affect initiation Misreading of genetic code o Wrong amino acid inserted o Causes the membrane to damage and bact. Dies. not absorbed from gut, often IV infusion Ineffective against anaerobes as transport of drug into cell requires oxygen resistance due to altered cell permeability or 30S binding site Streptomycin bactericidal, used to treat tuberculousmeningitis Side Effects: hearing loss (irreversible) and renal damage if taken for prolonged periods Resistance Production of enzyme to prevent binding to ribosome Binding site on ribosome changes Neomycin used topically very toxic if used systematically Gentamicin active against many G ve

Tetracyclines Binds reversibly to 30S ribosomal subunit distort A site, prevent tRNAfrom binding i.e. prevent tRNAfrom entering acceptor site on the ribosome Broad spectrum, bacteriostatic(reversible binding) suppress normal gut flora GI disturbance o diarrhea and overgrowth of drug-resistant bacteria and fungi also bind to eukaryotic ribosomes(less efficiently) affect development of bones and teeth o Brown staining of teeth deposition of drug as tetis a calcium chelator not suitable for children, pregnant women Resistance usually alteration of cell membrane to exclude drug

PROTEIN SYNTHESIS INHIBITOR Chloramphenicol

Microlides (Erythromycin)

Lincosamides

Mode of Action

binds to 50S subunit, inhibits peptide bond formation blocks elongation

binds to 50S ribosome, blocks the translocation step by preventing the release of the uncharged (or empty) tRNAfrom the donor site after the peptide bond is formed

Properties

Commonly bacteriostatic, bacteriocidalto S. pneumoniae, H. influenzaeand N. meningitides broad spectrum, can kill even anaerobic bacteria However can cause GI disturbance, overgrowth of C. albicans can occur small, polar; so oral administration possible crosses blood-brain barrier used to treat bacterial meningitis toxicity and resistance limit usefulness of drug Potential side-effects: Bone marrow toxicity (but reversible) and aplastic anemia toxic to neonates (immature liver) Grey baby syndrome

bacteriostatic, most active against G+vecells alternative to penicillin, especially for Strep infection side effects are mild, may cause nausea Resistance: due to altered ribosomaltarget site

active against anaerobes; penetrates bone useful for osteomyelitis Serious side effect potentially fatal pseudomembranousc olitis Caused by overgrowth of Clostridium difficilewhich produces necrotizing toxins C. difficileovergrows because it is always resistant to clindamycin

resistance common primarily due to enzymatic modification that prevents drug binding to ribosome

Antibiotic Aminoglycoside s

Ribosomal Subunit 30S

Mode of Action Blocks functioning of initiation complex and causes misreading of mRNA

Bactericidal or Bacteriostatic Bactericidal

Side Effects

Resistance due to altered cell permeability or 30S binding site

Tetracyclines

30S

Blocks tRNAbinding to ribosome

Bacteriostatic

Chloramphenic ol

50S

Blocks peptidyltransferase

Both

Erythromycin

50S

Blocks translocation

Primarily Bacteriostatic Primarily bacteriostatic

diarrhea and overgrowth of drugresistant bacteria and fungi affect development of alteration of cell membrane to bones and teeth o Brown staining exclude drug of teeth deposition of drug as tetis a calcium chelator enzymatic Bone marrow toxicity (but modification that reversible) and prevents drug aplasticanemia binding to ribosome due to altered Nausea ribosomaltarget site potentially fatal pseudomembranouscolitis

Clindamycin

50S

Blocks translocation

3. NUCLEIC ACID SYNTHESIS INHIBITORS DNA synthesis (replication) inhibitors Quinolones

Properties synthetic chemotherapeutic agents inactivate bacterial gyrase(= DNA topoisomeraseII) and topoisomerase enzymes that wind and unwind DNA dont bind to mammalian enzymes, minimal toxicity Resistance: due to alterations in DNA gyraseor cell membrane permeability for G-veenteric bacteria; sometimes used for UTI

Naladixic Acid

Fluoroquinolones have broader spectrum of activity (G +ve, G -ve, anaerobes)

RNA synthesis (transcription) inhibitors

Properties Rifampicin(Rifampin) o inactivates RNA polymerase, blocks mRNA synthesis - broad spectrum (GI disturbance) - effective against Mycobacterium tuberculosis - occasional side effects: liver damage, allergic reactions Resistance increasing o due to mutation of binding site on RNA polymerase Rifampicinis usually given in combination with other drugs because resistant mutants appear at a high rate when used alone

Rifamycins

Nucleotide synthesis inhibitors

Properties analogues of para-aminobenzoicacid (PABA), a precursor of tetrahydrofolicacid (THFA) o required for nucleotide synthesis in bacteria (mammals obtain THFA in diet) o competitive inhibitor, so bacteriostatic o active against G ve, so good for UTIs but resistance widespread

Sulfonamides

Trimethoprim Co-trimoxazole

acts at a later point in nucleotide synthesis pathway = Trimethoprim + sulfamethoxazole (sulfonamide) synergistic drug interaction; resistance less likely useful for long term prophylaxis of UTIs

4. BACTERIAL MEMBRANE DISRUPTORS depolarisebacterial membranes affect membrane transport processes, ATP synthesis Daptyomycinis useful against MRSA, VRE bactericidal, detergent-like action active against most G-veorganisms toxic to kidney and neural tissues topical use for G veinfections

Lipopeptides

Polymyxin B