Combined Efficacy of an Antimicrobial Cationic Peptide Polymer with Conventional Antibiotics to Combat Multidrug-Resistant Pathogens.,ACS Infectious Diseases

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Combined Efficacy of an Antimicrobial Cationic Peptide Polymer with Conventional Antibiotics to Combat Multidrug-Resistant Pathogens.
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2020-03-05 , DOI: 10.1021/acsinfecdis.0c00016
Kishore R V Thappeta ₁ , Yogesh S Vikhe ₂ , Adeline M H Yong _{1,

3} , Mary B Chan-Park ₂ , Kimberly A Kline _{1,

3}

Affiliation

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 Staphylococcus aureus (MRSA), MDR Escherichia coli, and vancomycin-resistant Enterococcus faecalis (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 E. coli, 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.

中文翻译：

抗菌阳离子肽聚合物与常规抗生素的综合功效，可对抗多种药物耐药的病原体。

到2050年，抗生素耐药性感染预计每年将导致全球1000万人死亡，并使全球经济损失100万亿美元。迫切需要新颖的方法和常规抗生素的替代品来对抗抗菌素耐药性。我们合成了一种基于壳聚糖的寡聚赖氨酸抗菌肽CSM5-K5（其中CSM代表壳聚糖单体重复单元，K代表赖氨酸氨基酸重复单元），其目标是耐多药（MDR）细菌物种。在这里，我们显示CSM5-K5对耐甲氧西林的金黄色葡萄球菌（MRSA），耐多药的大肠埃希菌和耐万古霉素的粪肠球菌（VRE）表现出快速的杀菌活性。将CSM5-K5与每种生物都具有抗药性的抗生素联合治疗，可恢复对常规抗生素的敏感性。单独使用CSM5-K5可以将预先形成的细菌生物膜减少2-4个数量级，并且与常规抗生素结合使用时，在亚抑制浓度下可以将预先形成的生物膜减少2-3个数量级以上。此外，使用小鼠切除伤口感染模型，CSM5-K5处理可将细菌负担减少1-3个数量级，并与奥沙西林，万古霉素和链霉素协同作用，分别清除MRSA，VRE和MDR大肠杆菌。重要的是，在连续传代的15天中，三种MDR细菌对CSM5-K5几乎没有抵抗力。此外，由于MRSA而引起的对CSM5-K5的低水平耐药性使对β-内酰胺类抗生素奥沙西林的敏感性增加（附带敏感性）。

更新日期：2020-03-05

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