Chromosome, Ribosome Inhibitors & Resistance

Fluoroquinolones mechanism

Inhibit bacterial topoisomerase II (DNA gyrase) & topoisomerase IV; block DNA unwinding & separation → bactericidal

Fluoroquinolones target difference

Gram-negatives = DNA gyrase (primary); Gram-positives = topoisomerase IV (primary)

Fluoroquinolone examples

Ciprofloxacin; Levofloxacin; Moxifloxacin; Ofloxacin

Fluoroquinolone resistance

Enzyme modification (reduced binding); Efflux pump upregulation

Rifampicin mechanism

Binds β-subunit of bacterial RNA polymerase; blocks initiation of transcription → mRNA synthesis prevented

Rifampicin resistance

Mutation altering β-subunit structure → drug cannot bind

Metronidazole mechanism

Nitro group reduced in low-redox bacterial/anaerobic environments → active metabolites cause DNA strand breakage

Metronidazole status

Prodrug; only active inside susceptible cells; used for anaerobes & parasites; alternative for severe mouth infections

Nitrofurantoin mechanism

Reduction generates reactive intermediates → DNA damage; most active in acidic urine; resistance rare

Ribosome subunits

Bacterial = 30S small + 50S large (70S total); Mammalian cytoplasmic = 40S + 60S (80S) → selective toxicity

tRNA binding sites

A = incoming aminoacyl-tRNA; P = peptide bond formation; E = exit site

Tetracyclines mechanism

Bind 30S subunit; block A site → prevent new tRNA attachment → protein synthesis halted; bacteriostatic

Tetracyclines resistance

Impaired uptake; Ribosomal protection/modification; Efflux pumps

Chloramphenicol mechanism

Bind 50S subunit; inhibit peptidyl transferase → no peptide bond formation

Chloramphenicol toxicity note

Also inhibits mitochondrial 50S → bone marrow suppression / rare aplastic anaemia; restricted use except topical for conjunctivitis

Chloramphenicol resistance

Enzymatic inactivation; Reduced uptake/efflux; Target modification

ENT infections & treatment

Bacterial conjunctivitis = chloramphenicol; Otitis media = macrolides; Sinusitis = macrolides/tetracyclines

Four general resistance mechanisms

Antibiotic inactivation; Reduced permeability/uptake; Target modification; Increased efflux

Intrinsic resistance definition

Natural inherent resistance of species; due to absence of target or impermeability; not acquired

Acquired resistance definition

Develops in previously susceptible cells via mutation or horizontal gene transfer

Three horizontal gene transfer mechanisms

Transformation; Transduction; Conjugation

Transformation

Uptake of naked free DNA from environment by competent cells; e.g., Streptococcus, Haemophilus, Neisseria

Transduction

DNA transfer via bacteriophage (virus); Generalized = any DNA region; Specialized = specific chromosomal region

Conjugation

Direct cell-to-cell contact via pilus; plasmid transferred; most important for rapid resistance spread