Repurposing PBT2 to overcome Gram-negative bacterial spesis: P. aeruginosa MS14403 Wild-Type. Pseudomonas aeruginosa strain:MS14403

The emergence of polymyxin resistance in carbapenem-resistant and extended-spectrum b-lactamase (ESBL)-producing bacteria is a significant threat to human health, and new treatment strategies are urgently required. Here we investigated the ability of the safe-for-human use ionophore PBT2 to restore antibiotic sensitivity in polymyxin-resistant, ESBL-producing, carbapenem-resistant Gram-negative human pathogens. PBT2 was observed to resensitize Klebsiella pneumoniae, Escherichia coli, Acinetobacter baumannii and Pseudomonas aeruginosa to last-resort polymyxin class antibiotics, including the less-toxic next-generation polymyxin derivative, FADDI-287. We were unable to select for mutants resistant to PBT2 + FADDI-287 in polymyxin resistant E. coli containing a plasmid-borne mcr-1 gene or K. pneumoniae carrying a chromosomal mgrB mutation. Using a highly invasive K. pneumoniae strain engineered for polymyxin resistance through mgrB mutation, we successfully demonstrated the efficacy of PBT2 + FADDI-287 in vivo for the treatment of Gram-negative sepsis. These data present a new treatment modality to break antibiotic resistance in high priority polymyxin-resistant Gram-negative pathogens.

耐碳青霉烯类且产超广谱β-内酰胺酶（extended-spectrum β-lactamase, ESBL）的细菌出现多粘菌素耐药性，对人类健康构成重大威胁，亟需全新治疗策略。本研究探究了经人体安全验证的离子载体PBT2恢复多粘菌素耐药、产ESBL且耐碳青霉烯类的革兰氏阴性人类病原菌抗生素敏感性的能力。实验观察到，PBT2可使肺炎克雷伯菌、大肠埃希菌、鲍曼不动杆菌及铜绿假单胞菌对最后一线多粘菌素类抗生素恢复敏感性，包括毒性更低的下一代多粘菌素衍生物FADDI-287。在携带质粒源性mcr-1基因的多粘菌素耐药大肠埃希菌，以及携带染色体mgrB突变的肺炎克雷伯菌中，未筛选出对PBT2联合FADDI-287产生耐药的突变株。使用经mgrB突变构建为多粘菌素耐药表型的高侵袭性肺炎克雷伯菌菌株，我们成功验证了PBT2联合FADDI-287在体内治疗革兰氏阴性菌败血症的疗效。本研究数据为破解高优先级多粘菌素耐药革兰氏阴性病原菌的抗生素耐药性问题提供了全新治疗范式。