Substrate Specificities and Efflux Efficiencies of RND Efflux Pumps of Acinetobacter baumannii
Substrate Specificities and Efflux Efficiencies of RND Efflux Pumps of Acinetobacter baumannii
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DOI：
10.1128/jb.00049-18
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发表时间：
2018-07-01
影响因子：
3.2
通讯作者：
Zgurskaya, Helen, I
中科院分区：
文献类型：
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作者：
Leus, Inga, V;Weeks, Jon W.;Zgurskaya, Helen, I
抗生素耐药鲍曼不动杆菌引起的感染是非常难以治疗的。在这些耐药谱中起重要作用的是多药外排泵，特别是那些属于耐药-增殖-细胞分裂（RND）转运蛋白超家族的泵。本文分析了A.鲍曼不动杆菌ATCC 17978。该菌株对抗生素敏感，并且不包含暴露于高浓度抗生素时通常选择的突变。我们构建了ATCC 17978的衍生物，缺乏染色体编码的RND泵，并通过质粒携带的基因补充这些菌株。我们分析了基板的选择性和效率的各个泵的背景下，天然的外膜和它们的hyperporinated变种。我们的研究结果表明，AdeIJK的失活提供了最强的增强抗生素活性，而AdeFGH的失活触发了AdeAB的过表达。质粒携带的过量生产补充了外排缺失突变体的超敏感表型，使其达到亲本ATCC 17978的水平。只有少数抗生素强烈受益于外排泵的过度产生，其中一些抗生素的抗菌活性取决于与外膜的低渗透性屏障的协同相互作用。过量生产或外排泵失活显著改变ATCC 17978的脂质组。我们的结论是A.鲍曼不动杆菌与该细菌的生理学紧密结合，并且鲍曼不动杆菌中的抗生素耐药性的临床水平。重要性RND型外排泵在鲍曼不动杆菌临床抗生素耐药性的发展中起重要作用。鲍曼不动杆菌。然而，它们的具体作用和对抗生素耐药性的贡献程度仍不清楚。通过分析抗生素在不同通透性屏障的菌株中的抗菌活性，发现主动外排在A.鲍曼不动杆菌仅限于几种选定的抗生素。我们的研究结果进一步表明，外排泵过度生产对抗生素敏感性的影响显着低于先前报道的临床分离株。另外的耐药机制，特别是那些改善细菌细胞的渗透屏障并与主动外排泵协同作用的机制，可能涉及临床A.鲍曼不动杆菌分离株。
Antibiotic-resistant Acinetobacter baumannii causes infections that are extremely difficult to treat. A significant role in these resistance profiles is attributed to multidrug efflux pumps, especially those belonging to the resistance-nodulation-cell division (RND) superfamily of transporters. In this study, we analyzed functions and properties of RND efflux pumps in A. baumannii ATCC 17978. This strain is susceptible to antibiotics and does not contain mutations that are commonly selected upon exposure to high concentrations of antibiotics. We constructed derivatives of ATCC 17978 lacking chromosomally encoded RND pumps and complemented these strains by the plasmid-borne genes. We analyzed the substrate selectivities and efficiencies of the individual pumps in the context of native outer membranes and their hyperporinated variants. Our results show that inactivation of AdeIJK provides the strongest potentiation of antibiotic activities, whereas inactivation of AdeFGH triggers the overexpression of AdeAB. The plasmid-borne overproduction complements the hypersusceptible phenotypes of the efflux deletion mutants to the levels of the parental ATCC 17978. Only a few antibiotics strongly benefitted from the overproduction of efflux pumps and antibacterial activities of some of those depended on the synergistic interaction with the low permeability barrier of the outer membrane. Either overproduction or inactivation of efflux pumps change dramatically the lipidome of ATCC 17978. We conclude that efflux pumps of A. baumannii are tightly integrated into physiology of this bacterium and that clinical levels of antibiotic resistance in A. baumannii isolates are unlikely to be reached solely due to the overproduction of RND efflux pumps.IMPORTANCE RND-type efflux pumps are important contributors in development of clinical antibiotic resistance in A. baumannii. However, their specific roles and the extent of contribution to antibiotic resistance remain unclear. We analyzed antibacterial activities of antibiotics in strains with different permeability barriers and found that the role of active efflux in antibiotic resistance of A. baumannii is limited to a few select antibiotics. Our results further show that the impact of efflux pump overproduction on antibiotic susceptibility is significantly lower than the previously reported for clinical isolates. Additional mechanisms of resistance, in particular those that improve the permeability barriers of bacterial cells and act synergistically with active efflux pumps are likely involved in antibiotic resistance of clinical A. baumannii isolates.