Travelers' Diarrhea-Associated Enterotoxigenic Escherichia coli gyrA Mutants and Quinolone Antibiotic Affinity: A Molecular Dynamics Simulation and Residue Interaction Network Analysis

Travelers' diarrhea (TD) is one of the most important global health issues among international travelers, especially those traveling to developing countries. Enterotoxigenic Escherichia coli (ETEC) is the most frequently isolated pathogen causing TD. Although TD is self-limiting, it is also severely incapacitating. Ciprofloxacin is one of the standard quinolone antibiotics used in patients with TD. However, the alarming levels of antibiotic resistance have necessitated the urgent need to identify new drugs. The drug target of ciprofloxacin is gyrA, which is exclusively present in prokaryotes and essential for bacterial survival. Several mutations in the quinolone resistance-determining region of gyrA are associated with increased quinolone resistance in vivo, which accounts for reduced affinity toward quinolones. To understand the molecular events underlying the mechanism of drug resistance, we report, for the first time to the best of our knowledge, the structural and dynamic effects of mutations in ETEC gyrA on ciprofloxacin affinity in comparison with the wild-type protein. Our simulations reveal that mutations significantly alter the gyrA residue interaction network and overall pattern of global dominant motions in major distinctive domains of N-terminal regions of gyrA. This study therefore provides important insights for the design of more potent antibacterial agents with high ligand efficacy for treating drug-resistant bacterial infections, including the TD that continues to adversely impact global health and international travel.