胍基修饰的抗菌高分子与抗生素的协同效应及其对细菌耐药性的影响

Due to the recent surge of antibiotic resistance, antibiotic monotherapy is no longer sufficient to treat multidrug-resistant (MDR) bacterial infections. Combination therapy of different antibiotics or antibiotic with nonantibiotic adjuvant is a potential solution. However, the clinical efficacy of the antibiotic combinations remains unclear, and their effects on development of antibiotic resistance are still unknown. Recently, we developed antimicrobial guanidinium-functionalized polycarbonates which exhibited strong in vivo antimicrobial activity and high selectivity (therapeutic index for A. baumannii infection: ED50/LD50=1473). More importantly, the polymers induced no drug resistance even after repeated treatment, which is probably due to the unique membrane lytic and membrane translocation action mechanisms of the poly(guanidiniums). Interestingly, the RNA-seq results further revealed that poly(guanidiniums) and antibiotic exerted opposite effects on regulation of ~78% common gene shared by bacteria treated with polymer and antibiotic, respectively. Inspired by these interesting findings, we propose combining antimicrobial poly(guanidiniums) and antibiotics to increase antibiotic uptake in bacteria with purpose of enhancing antibacterial activity and mitigation of antibiotic resistance. Our preliminary results indeed confirmed that poly(guanidiniums) have synergistic antimicrobial effect with four common antibiotics against MDR A. baumannii. In particular, the minimum inhibitory concentration of antibiotic rifampicin was reduced by ~2000 fold when it was combined with poly(guanidiniums). Further systematic investigation will be carried out to study in vitro and in vivo synergistic effects as well as action mechanism of antimicrobial poly(guanidiniums) and antibiotics against MDR Gram-negative bacteria, and to explore whether this combination can mitigate antibiotic resistance. We aim to provide a novel and effective antimicrobial polymer/antibiotic combination therapy for treatment of MDR infections.

单一抗生素疗法已不足以应对大量涌现的多重耐药菌，多抗生素或抗生素/非抗生素组合疗法是极具研究前景的解决方案，但抗生素组合对耐药菌的临床功效及其对耐药性影响仍然存疑。申请人与合作团队近期研发了兼具优异杀菌性能和低毒性的胍基修饰可降解高分子(治疗指数高达1473)，且其不会导致耐药性(Nature Communication,2018)。研究还发现高分子和抗生素对两者分别处理过的耐药菌有着相反的基因表达调控。受上述研究启发，我们提出高分子/抗生素组合疗法，以提高抗生素的摄入而增强抗生素对耐药菌的抗菌能力，并同时抑制细菌耐药性的产生和进化。预实验结果表明高分子可与四种抗生素产生协同抗菌效应，其中抗生素利福平的最低抑菌浓度可降低高达~2000倍。因此我们拟系统研究胍基修饰的抗菌高分子/抗生素组合对耐药菌的协同效应及其成因，并探索其对耐药性的抑制作用，以期为耐药菌感染提供一个全新有效的治疗方案。