Emergence of a Potent Multidrug Efflux Pump Variant That Enhances Campylobacter Resistance to Multiple Antibiotics.
Emergence of a Potent Multidrug Efflux Pump Variant That Enhances Campylobacter Resistance to Multiple Antibiotics.
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一种有效的多药外排泵变体的出现，可增强弯曲杆菌对多种抗生素的耐药性
DOI：
10.1128/mbio.01543-16
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发表时间：
2016-09-20
期刊：
影响因子：
6.4
通讯作者：
Shen J
中科院分区：
文献类型：
--
作者：
Yao H;Shen Z;Wang Y;Deng F;Liu D;Naren G;Dai L;Su CC;Wang B;Wang S;Wu C;Yu EW;Zhang Q;Shen J
细菌抗生素外排泵是抗生素耐药性的关键参与者。虽然它们在赋予多药耐药性中的作用是有据可查的，但增强细菌对多种药物的耐药性的“超级”外排泵变体的出现尚未报道。在这里，我们描述了弯曲杆菌，一种主要的人畜共患病原体，其对抗生素的耐药性被认为是美国严重的抗生素耐药性威胁的主要外排泵CmeABC的耐药性增强变体（命名为RE-CmeABC）的出现。与先前表征的CmeABC转运蛋白相比，RE-CmeABC在赋予弯曲杆菌对抗生素的抗性方面更有效，这通过增加的MIC和减少的抗生素细胞内积累来显示。结构建模表明，CmeB的药物结合口袋中的序列变化可能有助于增强外排功能。此外，RE-CmeABC扩大了环丙沙星的突变体选择窗口，增强了抗生素耐药突变体的出现，并赋予对氟喹诺酮类（一种用于临床治疗弯曲杆菌病的重要抗生素）极高水平的耐药性。此外，RE-CmeABC是水平可转移的，在临床分离株中改变抗生素MIC分布，并且在空肠弯曲杆菌分离株中越来越普遍，这表明它在抗微生物选择下具有适应性优势。这些发现揭示了增强多药耐药性的新机制和细菌适应多种抗生素选择的有效策略。细菌抗生素外排泵普遍存在于细菌生物体中，并通过将抗菌剂和其他有毒化合物挤出细胞来保护细菌免受抗菌剂和其他有毒化合物的抗菌作用。因此，这些外排转运蛋白代表了抗生素耐药性的重要机制。在这项研究中，我们发现了一种独特的外排泵变体的出现和日益增加的患病率，这种变体在抗生素的外排中更加强大，并在弯曲杆菌中产生多药耐药性，弯曲杆菌是一种通过食物链传播给人类的主要食源性病原体。与仅允许细菌抵抗特定抗菌剂的其他特定耐药决定因素不同，获得功能增强的外排泵将使细菌能够同时抵抗多种抗生素。这些发现揭示了一种以前未描述的增强多药耐药性的机制，并为我们了解细菌如何适应抗生素治疗开辟了新的方向。
Bacterial antibiotic efflux pumps are key players in antibiotic resistance. Although their role in conferring multidrug resistance is well documented, the emergence of “super” efflux pump variants that enhance bacterial resistance to multiple drugs has not been reported. Here, we describe the emergence of a resistance-enhancing variant (named RE-CmeABC) of the predominant efflux pump CmeABC in Campylobacter, a major zoonotic pathogen whose resistance to antibiotics is considered a serious antibiotic resistance threat in the United States. Compared to the previously characterized CmeABC transporters, RE-CmeABC is much more potent in conferring Campylobacter resistance to antibiotics, which was shown by increased MICs and reduced intracellular accumulation of antibiotics. Structural modeling suggests that sequence variations in the drug-binding pocket of CmeB possibly contribute to the enhanced efflux function. Additionally, RE-CmeABC expands the mutant selection window of ciprofloxacin, enhances the emergence of antibiotic-resistant mutants, and confers exceedingly high-level resistance to fluoroquinolones, an important class of antibiotics for clinical therapy of campylobacteriosis. Furthermore, RE-CmeABC is horizontally transferable, shifts antibiotic MIC distribution among clinical isolates, and is increasingly prevalent in Campylobacter jejuni isolates, suggesting that it confers a fitness advantage under antimicrobial selection. These findings reveal a new mechanism for enhanced multidrug resistance and an effective strategy utilized by bacteria for adaptation to selection from multiple antibiotics. Bacterial antibiotic efflux pumps are ubiquitously present in bacterial organisms and protect bacteria from the antibacterial effects of antimicrobials and other toxic compounds by extruding them out of cells. Thus, these efflux transporters represent an important mechanism for antibiotic resistance. In this study, we discovered the emergence and increasing prevalence of a unique efflux pump variant that is much more powerful in the efflux of antibiotics and confers multidrug resistance in Campylobacter, which is a major foodborne pathogen transmitted to humans via the food chain. Unlike other specific resistance determinants that only allow bacteria to resist a particular antimicrobial, the acquisition of a functionally enhanced efflux pump will empower bacteria with simultaneous resistance to multiple classes of antibiotics. These findings reveal a previously undescribed mechanism for enhanced multidrug resistance and open a new direction for us to understand how bacteria adapt to antibiotic treatment.