Role of acid responsive genes in the susceptibility of <i>Escherichia coli</i> to ciclopirox

다국어 초록 (Multilingual Abstract)

<P><B>Abstract</B></P> <P>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 <I>Escherichia coli</I> 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 <I>evgS</I> or <I>hns</I> 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.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Ciclopirox antibacterial activity was analysed by genome-wide expression profiling. </LI> <LI> Ciclopirox affects expression of glutamate-dependent acid resistance pathway genes. </LI> <LI> Down-regulation of <I>hns</I> transcription likely increases ciclopirox activity. </LI> <LI> Susceptibility to ciclopirox accompanies increased cell size and decreased motility. </LI> <LI> The findings identify probable pathways for ciclopirox action against <I>E. coli</I>. </LI> </UL> </P>