Antimicrobial Agents - Inhibition Of DNA And Protein Synthesis

Antimicrobial Agents - Inhibition of DNA and Protein Synthesis

Bacterial chromosome replication

DNA replication

Bacterial Topoisomerases 

maintain DNA in appropriate state of supercoiling 

cut and reseal DNA

DNA gyrase (topoisomerase II) introduces negative supercoils 

Topoisomerase IV decatenates circular chromosomes 

these are the targets of the quinolone antibacterial agents 

Quinolones

bind to bacterial DNA gyrase and topoisomerase IV after DNA strand breakage 

prevent resealing of DNA 

disrupt DNA replication and repair 

bactericidal (kill bacteria)

Fluoroquinolone is particularly useful against

Gram +ves: Staphylococcus aureus, streptococci 

Gram -ves: Enterobacteriacea; Pseudomonas aeruginosa 

Anaerobes: e.g. Bacteroides fragilis 

many applications e.g. UTIs, prostatitis, gastroenteritis, STIs 

Adverse effects

Relatively well tolerated

GI upset in ~ 5% of patients 

allergic reactions (rash, photosensitivity) in 1 - 2% of patients 

Inhibition of Bacterial Protein Synthesis 

Macrolides 

in 1952: Erythromycin was isolated as the first macrolide (Streptomyces erythreus) 

Newer macrolides: clarithromycin, azithromycin 

Structurally they consist of a lactone ring (14- to 16-membered) + two attached deoxy sugars 

Mode of action 

bind reversibly to bacterial 50S ribosomal subunit 

causes growing peptide chain to dissociate from ribosome → inhibiting protein synthesis 

bacteriostatic (stops reproduction)

Macrolides’ spectrum of activity

good antistaphylococcal and antistreptococcal activity 

treatment of respiratory & soft tissue infections and sensitive intracellular pathogens • e.g. Chlamydia, Legionella 

Adverse effects

Generally well tolerated

nausea 

vomiting 

diarrhoea 

rash 

Aminoglycosides

large family of antibiotics produced by various species of Streptomyces (“mycin”) and Micromonospora (“micin”) 

include: streptomycin, neomycin, kanamycin, gentamicins, tobramycin 

Structure = linked ring system composed of aminosugars and an aminosubstituted cyclic polyalcohol 

Mode of action of aminoglycosides

Bind irreversibly to 30S ribosomal subunit 

disrupt elongation of nascent peptide chain 

translational inaccuracy → defective proteins 

bactericidal 

Spectrum of activity 

broad spectrum; mainly aerobic G-ve bacilli (e.g. P. aeruginosa) 

used to treat serious nosocomial infections (hospital acquired infections)

First TB antibiotic

Used for cystic fibrosis 

Adverse effects

all aminoglycosides have low Therapeutic Index (only a small amount needed to become toxic)

renal damage, ototoxicity, loss of balance, nausea