History of Antimicrobials

Antimicrobial Drugs

Sulpha Drugs

• Compete with PABA for active site of bacterial dihydropteroate synthase
• Inhibit folate synthesis, leading to inhibition of DNA replication and protein synthesis
• Selectively toxic to bacteria and protozoa
• Humans do not contain dihydropteroate synthase enzyme, must obtain folic acid from diet
• Resistance: bacteria develop sulphonamide-resistant dihydropteroate synthase enzyme

Trimethoprim

• Competitive inhibitor of dihydrofolate reductase
• Interferes with folic acid production
• Often combined with sulpha drugs to increase efficacy of treatment
• Resistance: permeability barrier, efflux pumps, naturally resistant dihydrofolate reductase, and acquired resistance

Quinolones/Fluoroquinolones

• Contain a 4-quinolone ring
• Broad spectrum, effective against E. coli, Klebsiella pneumoniae, Neisseria, P. aeruginosa, S. aureus, and Streptococcus pyogenes
• Act by inhibiting bacterial DNA gyrase and topoisomerase
• Inhibit DNA replication, repair, and chromosome separation, leading to bacterial death
• Resistance: DNA mutations in gyrase and topoisomerase coding genes, increased efflux, and plasmid-mediated resistance genes

Fundamentals

Bacteriostatic vs Bactericidal

• Bacteriostatic: reversible inhibition of growth, regrowth after elimination of the drug
• Bactericidal: death of target organism, non-reversible effect
• Choice of drug depends on type of infection and immune status

Spectrum of Activity

• Narrow Spectrum: targets subset of pathogens
• Broad Spectrum: targets a wider group of pathogens
• Used for empirical therapy, polymicrobic infections, and prophylactic prevention of infections

Dosage and Route of Administration

• Dosage: amount of medication given during a certain time interval
• Route of Administration: oral, intravenous, or intramuscular injection
• Depends on patient mass, metabolism, and elimination needs to be taken into account

Drug Interactions

• Synergetic interactions: better efficacy than individual drugs
• Antagonistic interactions: harmful effects, varied depending on drugs involved
• Examples: trimethoprim and sulfamethoxazole, antagonism between antimicrobials and non-antimicrobials

Cell Wall Synthesis Inhibitors

Penicillin

• Targets cell wall synthesis mediated by penicillin-binding proteins (PBPs)
• Inhibits transglycosylation and transpeptidation, leading to osmotic lysis
• Bacteria producing β-lactamases hydrolyse the C-N bond in the β-lactam ring
• Semi-synthetic penicillins have a broader spectrum of activity

Cephalosporins

• Resemble penicillin in structure, containing a β-lactam ring
• Bind to PBPs, inhibiting transpeptidation and causing osmotic lysis
• Chemical difference provides increased resistance to enzymatic inactivation of β-lactamases
• Used as an alternative to penicillin

Carbapenems and Monobactams

• Inhibit transpeptidase activity of PBPs
• Carbapenem family includes semi-synthetic drugs with a broad spectrum of activity
• Monobactam aztreonam is a narrow spectrum antibacterial, active against gram-negative bacteria

Vancomycin

• Glycopeptide that binds to the D-alanyl-D-alanine end of the pentapeptide
• Prevents cell wall synthesis, leading to osmotic lysis
• Active against gram-positive bacteria, including Staphylococcus aureus
• Last resort for Staphylococcus aureus### Antibiotics and Protein Synthesis Inhibitors

Bacitracin

• A group of structurally similar peptide antibiotics
• Blocks the dephosphorylation of C55-isoprenyl pyrophosphate and bactoprenol pyrophosphate
• Prevents incorporation of peptidoglycan precursors into the cell wall
• Broad spectrum, including gram-positive organisms on the skin
• Nephrotoxic (damaging to kidneys)

Polymyxin

• Cyclic polypeptides that insert into the cell membrane
• Makes a pore in the cell membrane, increasing permeability leading to cell death
• Most active against gram-negative rods
• Valuable against Pseudomonas aeruginosa and other gram-negative bacilli

Protein Synthesis Inhibitors

Ribosome Structure

• Ribosomes made of rRNA and proteins
• Prokaryotes have 23S, 16S, and 5S rRNA
• 23S and 5S are part of the large ribosomal subunit
• 16S is part of the small ribosomal subunit
• mRNA binds to the 16S ribosomal subunit

Translation

• The small and large subunit form a structure that allows mRNA to move through the ribosome
• Amino acids are joined according to sequence on mRNA by tRNA
• tRNA is at P-site (peptidization site)
• Anticodon on tRNA is complementary to the sequence on mRNA
• 23S RNA forms peptide bonds between adjacent amino acids

Overview

• 80S cytoplasmic ribosomes in animal cells are structurally distinct from those found in bacterial cells
• Makes protein synthesis a good selective target for antibacterial drugs
• Therapeutic index is fairly high, but not as high as that of cell wall inhibitors

Aminoglycosides

• Contain cyclohexane ring and amino sugars
• Effective against gram-negative bacteria and Mycobacterium
• Toxic in high doses, causing deafness, renal damage, loss of balance, nausea, and allergic reactions
• Attaches irreversibly to the 30S subunit of bacterial ribosomes
• Blocks the reading of the genetic code on mRNA
• Impairs proofreading ability of the ribosomal complex

Tetracyclines

• Family of antibiotics with a common 4-ring benzene structure
• Bacteriostatic and broad spectrum
• Side effects limit their use, including phototoxicity, permanent discoloration of developing teeth, and liver toxicity
• Binds to the 30S subunit
• Inhibits aminoacyl-tRNA (tRNA with bound amino acid) to the A-site of the ribosome

Macrolides

• Has a lactone ring structure containing 12-22 carbons
• Broad spectrum and bacteriostatic
• Effective against gram-negative and few gram-positive bacteria
• Binds to the 23S rRNA of the 50S ribosomal subunit
• Inhibits peptide chain elongation

Chloramphenicol

• Broad spectrum activity
• Very toxic, reducing bone marrow function and leading to aplastic anaemia
• Binds to the 23S rRNA of the 50S ribosomal subunit
• Inhibits peptidyl transferase activity of the large ribosome

Lincosamines

• Broad spectrum activity against anaerobic bacteria
• Limited activity against aerobes
• Reversibly binds to the 50S ribosomal subunit
• Inhibits translocation of mRNA
• Prevents protein synthesis

Metabolic Antagonists

Introduction

• Antimetabolites block proper functioning of metabolic pathways
• Structurally similar to key enzyme substrate
• Compete with the authentic substrate for binding site on enzyme
• Different enough to prevent or block enzyme activity
• Broad spectrum and bacteriostatic

Sulpha drugs

• Structurally related to sulphanilamide (p-aminobenzoic acid/PABA)
• PABA is needed for folic acid synthesis and is an enzyme co-factor
• Folic acid is a precursor of purines and pyrimidines
• Bases used for DNA and RNA synthesis and other cellular constituents