Quantifying the Evolutionary Conservation of Genes Encoding Multidrug Efflux Pumps in the ESKAPE Pathogens To Identify Antimicrobial Drug Targets.
Quantifying the Evolutionary Conservation of Genes Encoding Multidrug Efflux Pumps in the ESKAPE Pathogens To Identify Antimicrobial Drug Targets.
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DOI：
10.1128/msystems.00024-18
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发表时间：
2018-05
期刊：
影响因子：
6.4
通讯作者：
Sistrom MJ
中科院分区：
文献类型：
--
作者：
Brooks LE;Ul-Hasan S;Chan BK;Sistrom MJ
耐药性细菌感染率的增加是当代最紧迫的全球健康问题之一。ESKAPE病原体组代表了这些感染的主要原因，并且外排泵表达的上调是这些病原体中耐药性的重要机制。这使得人们对开发外排泵抑制剂以对抗耐药性感染产生了极大的兴趣;然而，迄今为止还没有开发出广泛的治疗方法。我们的研究评估了抵抗力的一个经常被低估的方面进化选择的影响。我们评估了所有测序ESKAPE病原体中所有注释的外排基因的选择，为耐药细菌感染的外排靶向治疗的当前和未来发展提供了关键背景和见解。耐药性细菌感染率的增加是当代最紧迫的全球健康问题之一。ESKAPE病原体（屎肠球菌、金黄色葡萄球菌、肺炎克雷伯菌、鲍曼不动杆菌、铜绿假单胞菌和肠杆菌属）已被确定为多重耐药细菌感染的主要全球原因，并且多药外排（MEX）转运系统的过表达已被确定为促进ESKAPE病原体多重耐药演变的最关键机制之一。尽管努力开发外排泵抑制剂来对抗抗生素耐药性，但仍然需要确定未来研究的其他靶点。我们评估了来自所有注释ESKAPE生物基因组的110个MEX编码基因的进化压力。我们确定了几个MEX基因下稳定的选择代表的目标，可以促进广谱治疗与进化的限制，限制潜在的逃逸突变体的出现。我们还研究了MEX系统作为药物靶点的评价，证明了不同的选择可能是在开发有效治疗方法时遇到的一些问题的基础，特别是与金黄色葡萄球菌中的诺拉系统有关。本研究提供了ESKAPE病原体外排的全面进化背景，这将为评价外排系统作为抗生素靶标提供关键背景。重要性耐药性细菌感染率的增加是当代最紧迫的全球健康问题之一。ESKAPE病原体组代表了这些感染的主要原因，并且外排泵表达的上调是这些病原体中耐药性的重要机制。这使得人们对开发外排泵抑制剂以对抗耐药性感染产生了极大的兴趣;然而，迄今为止还没有开发出广泛的治疗方法。我们的研究评估了抵抗力的一个经常被低估的方面进化选择的影响。我们评估了所有测序ESKAPE病原体中所有注释的外排基因的选择，为耐药细菌感染的外排靶向治疗的当前和未来发展提供了关键背景和见解。
Increasing rates of antibiotic-resistant bacterial infection are one of the most pressing contemporary global health concerns. The ESKAPE pathogen group represents the leading cause of these infections, and upregulation of efflux pump expression is a significant mechanism of resistance in these pathogens. This has resulted in substantial interest in the development of efflux pump inhibitors to combat antibiotic-resistant infections; however, no widespread treatments have been developed to date. Our study evaluates an often-underappreciated aspect of resistance—the impact of evolutionary selection. We evaluate selection on all annotated efflux genes in all sequenced ESKAPE pathogens, providing critical context for and insight into current and future development of efflux-targeting treatments for resistant bacterial infections. Increasing rates of antibiotic-resistant bacterial infection are one of the most pressing contemporary global health concerns. The ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) have been identified as the leading global cause of multidrug-resistant bacterial infections, and overexpression of multidrug efflux (MEX) transport systems has been identified as one of the most critical mechanisms facilitating the evolution of multidrug resistance in ESKAPE pathogens. Despite efforts to develop efflux pump inhibitors to combat antibiotic resistance, the need persists to identify additional targets for future investigations. We evaluated evolutionary pressures on 110 MEX-encoding genes from all annotated ESKAPE organism genomes. We identify several MEX genes under stabilizing selection—representing targets which can facilitate broad-spectrum treatments with evolutionary constraints limiting the potential emergence of escape mutants. We also examine MEX systems being evaluated as drug targets, demonstrating that divergent selection may underlie some of the problems encountered in the development of effective treatments—specifically in relation to the NorA system in S. aureus. This study provides a comprehensive evolutionary context to efflux in the ESKAPE pathogens, which will provide critical context to the evaluation of efflux systems as antibiotic targets. IMPORTANCE Increasing rates of antibiotic-resistant bacterial infection are one of the most pressing contemporary global health concerns. The ESKAPE pathogen group represents the leading cause of these infections, and upregulation of efflux pump expression is a significant mechanism of resistance in these pathogens. This has resulted in substantial interest in the development of efflux pump inhibitors to combat antibiotic-resistant infections; however, no widespread treatments have been developed to date. Our study evaluates an often-underappreciated aspect of resistance—the impact of evolutionary selection. We evaluate selection on all annotated efflux genes in all sequenced ESKAPE pathogens, providing critical context for and insight into current and future development of efflux-targeting treatments for resistant bacterial infections.