New insights into resistance of Helicobacter pylori against third- and fourth-generation fluoroquinolones: A molecular docking study of prevalent GyrA mutations
Abstract
BACKGROUND: Fluoroquinolones hinder bacterial DNA replication by inhibiting DNA gyrase. However, mutations, in the QRDR segment of its A subunit (GyrA), cause antibiotic resistance. Here, the interactions of levofloxacin (LVX), gemifloxacin (GXN), and moxifloxacin (MXN) with Helicobacter pylori GyrA, in LVX-resistant vs -sensitive strains, were studied.
METHODS: Levoflixacin-sensitive (n = 4) and -resistant (n = 9) H pylori strains, randomly selected from another antibiotic susceptibility study, underwent PCR amplification of gyrA gene, spanning the QRDR segment. The amplified gene fragments were sequenced and aligned. The homology model of H pylori GyrA was built based on that of Escherichia coli, and energy minimization was done. The interaction patterns of LVX, GXN, and MXN with GyrA were analyzed via molecular docking studies.
RESULTS: Sequence alignment of the 13 studied strains, created 5 categories of strains: (A) wild type-like (H pylori ATCC26695), (B) N87K-only, (C) D91N-only, (D) N87K + V94L, and (E) D91N + A97V mutations. The minimum inhibitory concentrations (MIC) for LVX-sensitive (category A) and -resistant (categories B-E) strains were <1 mg/L and ≥32 mg/L, respectively. The binding mode of GyrA in category A with LVX identified G35/N87/Y90/D91/V94/G114/S115/I116/D117/G118/D119, as key residues, some residing outside the QRDR segment. Category B strains lost only one interaction (G35), which led to elevated binding free energy (∆G) and full LVX resistance.…
Read the paper
Related studies
- Ferulic acid regulates the AKT/GSK-3β/CRMP-2 signaling pathway in a middle cerebral artery occlusion animal model
- Novel Pharmacokinetic/Pharmacodynamic Parameters Quantify the Exposure–Effect Relationship of Levofloxacin against Fluoroquinolone-Resistant Escherichia coli
- Photochemical behavior of levofloxacin
- Correlation Between Dissolution Profiles of Salt-Form Drugs in Biorelevant Bicarbonate Buffer and Oral Drug Absorption: Importance of Dose/ Fluid Volume Ratio
- Evaluation of the synergistic potential and mechanisms of action for de novo designed cationic antimicrobial peptides
- Synthesis of [11C]levofloxacin
Go deeper in Evidence Hub
Evidence Hub adds a study data sheet (design, sample size, evidence level, key numbers), an AI summary and a chat grounded in the paper's text.