Infectious Diseases Translational Research Programme, Department of Biochemistry, National University of Singapore, Singapore, Singapore.
School of Chemistry, Chemical and Biotechnology, Nanyang Technological University, Singapore, Singapore.
J Antimicrob Chemother. 2023 Oct 3;78(10):2581-2590. doi: 10.1093/jac/dkad274.
The rise of MDR Gram-negative bacteria (GNB), especially those resistant to last-resort drugs such as carbapenems and colistin, is a global health risk and calls for increased efforts to discover new antimicrobial compounds. We previously reported that polyimidazolium (PIM) compounds exhibited significant antimicrobial activity and minimal mammalian cytotoxicity. However, their mechanism of action is relatively unknown. We examined the efficacy and mechanism of action of a hydrophilic PIM (PIM5) against colistin- and meropenem-resistant clinical isolates.
MIC and time-kill testing was performed for drug-resistant Escherichia coli and Klebsiella pneumoniae clinical isolates. N-phenyl-1-naphthylamine and propidium iodide dyes were employed to determine membrane permeabilization. Spontaneous resistant mutants and single deletion mutants were generated to understand potential resistance mechanisms to the drug.
PIM5 had the same effectiveness against colistin- and meropenem-resistant strains as susceptible strains of GNB. PIM5 exhibited a rapid bactericidal effect independent of bacterial growth phase and was especially effective in water. The polymer disrupts both the outer and cytoplasmic membranes. PIM5 binds and intercalates into bacterial genomic DNA upon entry of cells. GNB do not develop high resistance to PIM5. However, the susceptibility and uptake of the polymer is moderately affected by mutations in the two-component histidine kinase sensor BaeS. PIM5 has negligible cytotoxicity on human cells at bacterial-killing concentrations, comparable to the commercial antibiotics polymyxin B and colistin.
PIM5 is a potent broad-spectrum antibiotic targeting GNB resistant to last-resort antibiotics.
耐多药革兰氏阴性菌（GNB）的出现，尤其是那些对碳青霉烯类和黏菌素等最后手段药物具有耐药性的细菌，对全球健康构成了威胁，因此需要加大力度开发新的抗菌化合物。我们之前曾报道过，多咪唑（PIM）化合物具有显著的抗菌活性和最小的哺乳动物细胞毒性。然而，其作用机制尚不清楚。我们研究了一种亲水性 PIM（PIM5）对多黏菌素和美罗培南耐药临床分离株的疗效和作用机制。
对耐多黏菌素和美罗培南的大肠杆菌和肺炎克雷伯菌临床分离株进行 MIC 和时间杀伤试验。使用 N-苯基-1-萘胺和碘化丙啶染料来确定细胞膜通透性。通过自发耐药突变和单缺失突变来了解该药物潜在的耐药机制。
PIM5 对多黏菌素和美罗培南耐药株的效果与 GNB 敏感株相同。PIM5 具有快速杀菌作用，不受细菌生长阶段的影响，在水中尤其有效。该聚合物破坏了外膜和细胞质膜。聚合物进入细胞后会与并插入细菌基因组 DNA 结合。GNB 不会对 PIM5 产生高耐药性。但是，该聚合物的敏感性和摄取会受到双组分组氨酸激酶传感器 BaeS 突变的适度影响。在杀菌浓度下，PIM5 对人细胞的细胞毒性可忽略不计，与商业抗生素多黏菌素 B 和黏菌素相当。
PIM5 是一种针对多黏菌素和美罗培南耐药的革兰氏阴性菌的有效广谱抗生素。
