PPEF treatment did not cause target specific mutation instead it leads to up-regulation of efflux gene in E. PPEF (bisbenzimidazole) targeting topoisomerase IA is observed to be an effective bactericidal agent against both Gram-positive and Gram-negative bacterial strains and thus can be developed as potent broad-spectrum antibiotic against MDR strains. This study constitutes a unique demonstration of efflux-based high-level colistin hetero-resistance, controlled by a soxRS regulator in Gram-negative bacteria.Īctivation of efflux systems and the formation of biofilm are majorly adapted by microbes to resist antimicrobial agents. Our observations highlight the importance of such findings, which previously were only superficially described because of the challenges associated with their detection, in the context of common modes of colistin resistance in Gram-negative bacteria. Transcriptional analysis results were further verified as demonstrating the development of hetero-resistance in colistin-susceptible strains by plasmid-based overexpression of soxRS. Transcriptional analysis further found that naturally elevated soxRS triggers the induction of the acrAB-tolC efflux pump proteins followed by the development of colistin hetero-resistance in E. Genomic analysis of mutant clones generated by transposome mutagenesis suggests that hetero-resistance is linked with overexpression of the acrAB-tolC efflux pump. Several approaches (WGS, transposome mutagenesis and RT-PCR analysis) were used to discover the molecular mechanism of colistin hetero-resistance. To characterize the molecular mechanism of colistin hetero-resistance in Enterobacter spp. cloacae is an intestinal commensal bacterium and a well-known opportunistic nosocomial pathogen. During a routine surveillance project on antimicrobial resistance, we found abnormal colistin-resistant Enterobacter asburiae and Enterobacter cloacae isolates. Several types of resistance to colistin have been identified, including hetero-resistance, which has been observed in several Gram-negative pathogens. Colistin is the last drug option for the treatment of MDR Gram-negative bacterial infections.
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