title: Investigation of Nalidixic Acid Resistance Mechanism in Salmonella enterica Using Molecular Simulation Techniques.
abstract: The emergence of nalidixic acid-resistant strains of Salmonella typhimurium remains to be a major public health problem. In particular, the substitution of Asn in place of Asp at the 87 loci in the GyrA of S. typhimurium was experimentally stated for nalidixic acid resistance. However, the data on the possible mechanism of nalidixic acid resistance are limited. In this study, I-Mutant2.0 and DUET program were employed to explore the impact of mutation on the stability of GyrA protein. Subsequently, molecular simulation techniques were employed to provide detailed information on the nalidixic acid-resistant associates with the D87N mutation in the GyrA of S. typhimurium. The binding free energy data depicts that nalidixic acid forms stable complex only with native-type GyrA than mutant (D87N) type GyrA protein. Moreover, our results theoretically suggest that hydrogen bonding formed by the Arg91 is certainly responsible for the GyrA of S. typhimurium drug selectivity. It is hoped that these evidences are immensely important for the development of new antibiotic and to overcome the nalidixic acid resistance in the near future.
authors.affiliation: Industrial Biotechnology Division, School of Bio Sciences and Technology, VIT University, Vellore, 632014, Tamil Nadu, India.
authors.forename: B
authors.initials: B
authors.lastname: Preethi
authors.forename: V
authors.initials: V
authors.lastname: Shanthi
authors.forename: K
authors.initials: K
authors.lastname: Ramanathan
mesh_terms: D001665:Binding Sites; D027081:DNA Gyrase / Q000737:chemistry / Q000235:genetics; D024881:Drug Resistance, Bacterial / Q000187:drug effects* / Q000235:genetics; D006860:Hydrogen Bonding; D056004:Molecular Dynamics Simulation; D009154:Mutation / Q000235:genetics; D009268:Nalidixic Acid / Q000494:pharmacology*; D010802:Phylogeny; D055550:Protein Stability / Q000187:drug effects; D019779:Salmonella enterica / Q000187:drug effects*; D013816:Thermodynamics; D013997:Time Factors
chemical_list: D009268:Nalidixic Acid; D027081:DNA Gyrase