Mutations in the superoxide-responsive regulator SoxR confer fluoroquinolone resistance in Stenotrophomonas maltophilia
Abstract
Stenotrophomonas maltophilia is a multidrug-resistant Gram-negative opportunistic pathogen. Its antimicrobial resistance arises from intrinsic traits and acquired mechanisms. Overexpression of drug efflux transporters is one of the key mechanisms mediating high-level antibiotic resistance. These transporters are regulated by transcriptional factors, including SoxR, a superoxide-responsive regulator containing an iron-sulfur [2Fe-2S] cluster. SoxR controls the multidrug efflux pumps MfsA and SmeVWX, as well as superoxide dismutase SodA1. To examine how soxR mutations affect antimicrobial resistance, random mutagenesis was performed, and mutated genes were ectopically expressed in a ΔsoxR mutant. Transformants were selected for ciprofloxacin resistance, a substrate for both MfsA and SmeVWX. Sequencing of 21 resistant colonies revealed five distinct mutation patterns (A-E), each containing multiple mutations. The ΔsoxR mutant expressing these soxR variants showed increased resistance to multiple antibiotics targeted by the efflux pumps, correlating with elevated MfsA and SmeVWX expression. This indicates constitutive SoxR activation. To assess the role of the [2Fe-2S] cluster, cysteine-to-serine substitutions at three of the four cluster-binding residues abolished SoxR's ability. Computational structure prediction and molecular dynamics simulations supported these findings, revealing that mutations enhanced solvent exposure of the [2Fe-2S] cluster. This suggests that the…
Read the paper
Related studies
- Synthesis, In Vitro and In Silico Molecular Docking Studies of Novel Phthalimide–Pyrimidine Hybrid Analogues to Thalidomide as Potent Antitubercular Agents
- Exploring the inhibitory performance of expired moxifloxacin and norfloxacin on copper corrosion in saline environment
- Molecular investigation of antimicrobial peptides against Helicobacter pylori proteins using a peptide-protein docking approach
- Screening of novel narrow-spectrum benzofuroxan derivatives for the treatment of multidrug-resistant tuberculosis through in silico, in vitro, and in vivo approaches
- Synthesis, Characterization, Anticancer, Antioxidant, and In Silico Evaluation of Semicarbazides and Thiosemicarbazides
- Fast and accurate prediction of drug induced proarrhythmic risk with sex specific cardiac emulators
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.