Centre for Microbial Diseases and Immunity Research, Department of Microbiology and Immunology, University of British Columbia, Vancouver, Canada.
Centre for Microbial Diseases and Immunity Research, Department of Microbiology and Immunology, University of British Columbia, Vancouver, Canada
Antimicrob Agents Chemother. 2019 Sep 23;63(10). doi: 10.1128/AAC.00935-19. Print 2019 Oct.
Infections caused by drug-resistant Gram-negative bacilli are a severe global health threat, limiting effective drug choices for treatment. In this study, polymyxin analogs designed to have reduced nephrotoxicity, direct activity, and potentiating activity were assessed for inhibition and outer membrane interaction kinetics against wild-type (WT) and polymyxin or multidrug-resistant (MDR) , , , and In MIC assays, two polymyxin B (PMB) analogs (SPR1205 and SPR206) and a polymyxin E analog (SPR946), with shortened peptide side chains and branched aminobutyryl N termini, exhibited promising activity compared with PMB and previously tested control polymyxin analogs SPR741 and polymyxin B nonapeptide (PMBN). Using dansyl-polymyxin (DPX) binding to assess the affinity of interaction with lipopolysaccharide (LPS), purified or in the context of intact cells, SPR206 exhibited similar affinities to PMB but higher affinities than the other SPR analogs. Outer membrane permeabilization measured by the 1--phenyl-napthylamine (NPN) assay did not differ significantly between the polymyxin analogs. Moreover, Hill numbers were greater than 1 for most of the compounds tested on and strains which indicates that the disruption of the outer membrane by one molecule of compound cooperatively enhances the subsequent interactions of other molecules against WT and MDR strains. The high activity demonstrated by SPR206 as well as its ability to displace LPS and permeabilize the outer membrane of multiple strains of Gram-negative bacilli while showing cooperative potential with other membrane disrupting compounds supports further research with this polymyxin analog.
耐药革兰氏阴性杆菌引起的感染是严重的全球健康威胁，限制了治疗的有效药物选择。在这项研究中，评估了设计为降低肾毒性、直接活性和增强活性的多粘菌素类似物对野生型（WT）和多粘菌素或多药耐药（MDR）、、、和的抑制和外膜相互作用动力学。在 MIC 测定中，两种多粘菌素 B（PMB）类似物（SPR1205 和 SPR206）和一种多粘菌素 E 类似物（SPR946），其肽侧链缩短，支化氨丁酰 N 端，与 PMB 相比表现出有希望的活性，以及之前测试过的对照多粘菌素类似物 SPR741 和多粘菌素 B 九肽（PMBN）。使用丹磺酰多粘菌素（DPX）结合评估与脂多糖（LPS）相互作用的亲和力，无论是在纯化状态还是在完整细胞中，SPR206 与 PMB 表现出相似的亲和力，但比其他 SPR 类似物的亲和力更高。通过 1--苯基-萘基胺（NPN）测定测量的外膜通透性在多粘菌素类似物之间没有显著差异。此外，对于和菌株，大多数化合物的希尔数大于 1，这表明一个化合物对外膜的破坏通过协同作用增强了其他分子随后与 WT 和 MDR 菌株相互作用的能力。SPR206 表现出的高活性以及其能够置换 LPS 和使多种革兰氏阴性杆菌的外膜通透性的能力，同时显示出与其他破坏膜的化合物具有协同潜力，支持对这种多粘菌素类似物进行进一步研究。
