The priority pathogen list published by the World Health Organization (WHO) has categorized carbapenem-resistant Acinetobacter baumannii and Pseudomonas aeruginosa as the top two critical pathogens, and hence, the development of novel antibacterial strategies to tackle such bacteria is highly necessary. Toward this aim, herein we report the efficacy of the combination of a lysine-based membrane-active small molecule, D-LANA-14 (d-lysine conjugated aliphatic norspermidine analogue bearing tetradecanoyl chain) and the obsolete/inactive antibiotics (such as tetracycline and rifampicin) to combat these superbugs. The combination of D-LANA-14 and the antibiotics tetracycline or rifampicin showed not only synergistic activity against growing planktonic cells of meropenem-resistant A. baumannii and P. aeruginosa clinical isolates but was also able to disrupt their established biofilms. More importantly, this synergistic effect was retained under the in vivo scenario, wherein the combination showed excellent efficacy in mice model of burn-wound infection with a drastic reduction of bacterial burden. A combined treatment of D-LANA-14 (40 mg/kg) and rifampicin (40 mg/kg) showed 4.9 log and 4.0 log reduction in A. baumannii and P. aeruginosa viability, respectively. On the contrary, individual treatment of D-LANA-14 decreased bacterial burden by 2.3 log (A. baumannii) and 1.3 log (P. aeruginosa) and rifampicin reduced about 3.0 log (A. baumannii) and 1.6 log (P. aeruginosa). Owing to the membrane-active nature imparted by D-LANA-14, bacteria could not develop resistance against the combined treatment, whereas a high-level of resistance development was observed against the last resort Gram-negative antibiotic, colistin. Taken together, the results therefore indicate a great potential of this novel combination to be developed as therapeutic regimen to combat infections caused by critical Gram-negative pathogens.

中文翻译：

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基于赖氨酸的小分子能使利福平和四环素对耐多药鲍曼不动杆菌和铜绿假单胞菌敏感。

世界卫生组织（WHO）发布的优先病原体清单已将耐碳青霉烯的鲍曼不动杆菌和铜绿假单胞菌归为最重要的两种病原体，因此，迫切需要开发出新颖的抗菌策略来应对此类细菌。为了实现这一目标，我们在此报告了基于赖氨酸的膜活性小分子D-LANA-14（带有十四烷酰基链的d-赖氨酸共轭脂肪族降鸟精idine类似物）和陈旧/无活性的抗生素（如四环素）的组合疗效和rifampicin）来对抗这些超级细菌。D-LANA-14和抗生素四环素或利福平的组合不仅显示出抗美罗培南耐药鲍曼不动杆菌和拟南芥P. 铜绿假单胞菌临床分离株，但也能够破坏其已建立的生物膜。更重要的是，这种协同作用在体内情况下得以保留，其中该组合在烧伤感染的小鼠模型中显示出优异的功效，并大大降低了细菌负担。D-LANA-14（40 mg / kg）和利福平（40 mg / kg）的联合处理分别显示鲍曼不动杆菌和铜绿假单胞菌的活力分别降低了4.9 log和4.0 log。相反，对D-LANA-14的单独处理将细菌负担降低了2.3 log（鲍曼不动杆菌）和1.3 log（铜绿假单胞菌），而利福平减少了约3.0 log（鲍曼不动杆菌）和1.6 log（铜绿假单胞菌）。 。由于D-LANA-14具有膜活性，细菌无法对联合处理产生抗药性，而观察到对最后一种革兰氏阴性抗生素大肠菌素的高水平耐药性发展。综上所述，结果因此表明该新型组合具有很大的潜力，可以作为治疗方案来对抗由革兰氏阴性病原体引起的感染。