AI Article Synopsis
- Antibiotic resistance is a significant challenge in treating bacterial infections, prompting researchers to explore repurposing existing drugs like ciclopirox, an antifungal that also hampers the growth of Gram-negative bacteria.
- Ciclopirox targets genes related to galactose metabolism and LPS biosynthesis, which may help to increase its effectiveness against certain bacteria by exploiting their genetic vulnerabilities.
- This study's use of genome-wide mRNA profiling identified GDAR genes that, when down-regulated (specifically evgS or hns), enhance E. coli's susceptibility to ciclopirox, ultimately providing insights into improving treatments for resistant bacterial strains.
Article Abstract
Antibiotic resistance poses a huge threat to the effective treatment of bacterial infections. To circumvent the limitations in developing new antibiotics, researchers are attempting to repurpose pre-developed drugs that are known to be safe. Ciclopirox, an off-patent antifungal agent, inhibits the growth of Gram-negative bacteria, and genes involved in galactose metabolism and lipopolysaccharide (LPS) biosynthesis are plausible antibacterial targets for ciclopirox, since their expression levels partially increase susceptibility at restrictive concentrations. In the present study, to identify new target genes involved in the susceptibility of Escherichia coli to ciclopirox, genome-wide mRNA profiling was performed following ciclopirox addition at sublethal concentrations, and glutamate-dependent acid resistance (GDAR) genes were differentially regulated. Additional susceptibility testing, growth analyses and viability assays of GDAR regulatory genes revealed that down-regulation of evgS or hns strongly enhanced susceptibility to ciclopirox. Further microscopy and phenotypic analyses revealed that down-regulation of these genes increased cell size and decreased motility. Our findings could help to maximise the efficacy of ciclopirox against hard-to-treat Gram-negative pathogens.
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| http://dx.doi.org/10.1016/j.bbrc.2018.04.063 | DOI Listing |
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