Singapore Centre for Environmental Life Science Engineering, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551.
School of Chemical and Biomedical Engineering, Nanyang Technological University, Singapore 637459.
ACS Infect Dis. 2020 May 8;6(5):1228-1237. doi: 10.1021/acsinfecdis.0c00016. Epub 2020 Mar 13.
Antibiotic-resistant infections are predicted to kill 10 million people worldwide per year by 2050 and to cost the global economy 100 trillion USD. Novel approaches and alternatives to conventional antibiotics are urgently required to combat antimicrobial resistance. We have synthesized a chitosan-based oligolysine antimicrobial peptide, CSM5-K5 (where CSM denotes chitosan monomer repeat units and K denotes lysine amino acid repeat units), that targets multidrug-resistant (MDR) bacterial species. Here, we show that CSM5-K5 exhibits rapid bactericidal activity against methicillin-resistant (MRSA), MDR , and vancomycin-resistant (VRE). Combinatorial therapy of CSM5-K5 with antibiotics to which each organism is otherwise resistant restores sensitivity to the conventional antibiotic. CSM5-K5 alone significantly reduced preformed bacterial biofilm by 2-4 orders of magnitude and, in combination with conventional antibiotics, reduced preformed biofilm by more than 2-3 orders of magnitude at subinhibitory concentrations. Moreover, using a mouse excisional wound infection model, CSM5-K5 treatment reduced bacterial burdens by 1-3 orders of magnitude and acted synergistically with oxacillin, vancomycin, and streptomycin to clear MRSA, VRE, and MDR , respectively. Importantly, little to no resistance against CSM5-K5 arose for any of the three MDR bacteria during 15 days of serial passage. Furthermore, low level resistance to CSM5-K5 that did arise for MRSA conferred increased susceptibility (collateral sensitivity) to the β-lactam antibiotic oxacillin. This work demonstrates the feasibility and benefits of using this synthetic cationic peptide as an alternative to, or in combination with, traditional antibiotics to treat infections caused by MDR bacteria.
到 2050 年，预计全球每年将有 1000 万人死于抗生素耐药性感染，全球经济将为此损失 100 万亿美元。为了应对抗微生物药物耐药性，迫切需要新的方法和替代传统抗生素的方法。我们已经合成了一种壳聚糖基寡聚赖氨酸抗菌肽 CSM5-K5（其中 CSM 表示壳聚糖单体重复单元，K 表示赖氨酸氨基酸重复单元），它针对多药耐药（MDR）细菌。在这里，我们表明 CSM5-K5 对耐甲氧西林金黄色葡萄球菌（MRSA）、MDR 和万古霉素耐药（VRE）具有快速杀菌活性。CSM5-K5 与每种生物体原本耐药的抗生素联合治疗可恢复对传统抗生素的敏感性。CSM5-K5 单独使用可将已形成的细菌生物膜减少 2-4 个数量级，与传统抗生素联合使用时，在亚抑菌浓度下可将已形成的生物膜减少 2-3 个数量级以上。此外，使用小鼠切口感染模型，CSM5-K5 治疗可将细菌负荷减少 1-3 个数量级，与苯唑西林、万古霉素和链霉素协同作用，分别清除 MRSA、VRE 和 MDR。重要的是，在 15 天的连续传代过程中，三种 MDR 细菌对 CSM5-K5 的耐药性几乎没有增加。此外，MRSA 对 CSM5-K5 产生的低水平耐药性赋予了对β-内酰胺类抗生素苯唑西林更高的敏感性（交叉敏感性）。这项工作证明了使用这种合成阳离子肽作为传统抗生素的替代物或联合使用来治疗 MDR 细菌引起的感染的可行性和益处。
