Basic NitrogenousHeterocyclic Rings at the 7‑Positionof Fluoroquinolones Foster Their Induction of Antibiotic Resistancein <i>Escherichia coli</i>

The extensive prescription of fluoroquinolone antibiotics has resulted in their ubiquitous presence in the environment, fueling the ongoing development of antibiotic resistance. Besides antibiotics, fluoroquinolone production intermediates, an overlooked category of pollutants that oftentimes possess the intact fluoroquinolone core structure, may also contribute to this public health crisis. To assess their relative potency and collectively examine the structural effects of fluoroquinolones on resistance development, wild-type <i>Escherichia coli</i> K12 was exposed to ten fluoroquinolone antibiotics and five intermediates at their environmentally relevant concentrations for 30 days. Phenotypic resistance alterations revealed that the absence of the C7 ring system in fluoroquinolones significantly impaired their capacity to induce resistance in <i>E. coli</i>, potentially due to diminished oxidative DNA damage and gyrase-mediated dsDNA breaks. Genetic and transcriptional analyses indicated that a uniform resistance mechanism emerged under both antibiotic and intermediate stress. Quantitative structure–activity relationship (QSAR) analysis further emphasized the positive impact of both basic nitrogenous heterocyclic rings at C7 (particularly the hydrogen-bond-donor pharmacophores) and aromatic rings at N1 in promoting resistance development, while highlighting the adverse effects of hydrophobic and hydrogen-bond-donor groups at N1. A robust QSAR model was developed and applied to assess the relative risks of other 105 fluoroquinolones. This study underscored the direct role of fluoroquinolone production intermediates in promoting environmental antibiotic resistance and illustrated how different structural features of fluoroquinolone pollutants will influence this process, offering theoretical insights for future antibiotic design and environmental regulation efforts.