Department of Chemistry and Chemistry Institute for Functional Materials, Pusan National University, Busan 46241, Republic of Korea.
Department of Chemistry and Chemistry Institute for Functional Materials, Pusan National University, Busan 46241, Republic of Korea.
Biochem Biophys Res Commun. 2018 Jun 2;500(2):296-301. doi: 10.1016/j.bbrc.2018.04.063. Epub 2018 Apr 13.
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.
抗生素耐药性对有效治疗细菌感染构成巨大威胁。为了规避开发新抗生素的局限性，研究人员正试图重新利用已开发且已知安全的药物。环吡酮胺是一种已过专利期的抗真菌药物，能够抑制革兰氏阴性菌的生长，而参与半乳糖代谢和脂多糖（LPS）生物合成的基因可能是环吡酮胺的潜在抗菌靶点，因为它们的表达水平在限制浓度下部分增加了易感性。在本研究中，为了鉴定与环吡酮胺对大肠杆菌易感性相关的新靶基因，在亚致死浓度下添加环吡酮胺后进行了全基因组 mRNA 谱分析，发现谷氨酸依赖的酸抗性（GDAR）基因存在差异表达。对 GDAR 调控基因的进一步药敏试验、生长分析和活力测定显示，evgS 或 hns 的下调强烈增强了对环吡酮胺的敏感性。进一步的显微镜和表型分析表明，这些基因的下调增加了细胞大小并降低了运动性。我们的研究结果有助于最大限度地提高环吡酮胺对难以治疗的革兰氏阴性病原体的疗效。
