Fluoroquinolones inhibit DNA gyrase in gram-negative bacteria and topoisomerase IV in gram-positive bacteria. Resistance mutations emerge in the 'quinolone resistance-determining region' (QRDR). The FIRST step mutation in E. coli that confers the LOWEST level of fluoroquinolone resistance occurs in which gene?

• A parC (encoding topoisomerase IV subunit C)
• B ompF (encoding outer membrane porin F)
• C marA (encoding multiple antibiotic resistance regulator)
• D gyrA (encoding DNA gyrase subunit A) ✓

Explanation

In E. coli (gram-negative), DNA gyrase is the primary target and topoisomerase IV is the secondary target of fluoroquinolones. First-step resistance mutations in the QRDR of gyrA (specifically at codon 83 Ser→Leu and codon 87 Asp→Asn) cause low-level resistance by reducing fluoroquinolone affinity for the drug-enzyme-DNA ternary complex. Subsequent mutations in parC provide additional resistance. OmpF porin loss reduces drug influx and marA upregulates efflux pumps, but these typically complement rather than initiate primary chromosomal resistance. Understanding this sequential mutation pathway explains why fluoroquinolone resistance develops stepwise with sub-therapeutic dosing.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.