Aminoglycoside heteroresistance in Enterobacter cloacae is driven by the cell envelope stress response.

IF 5.1 1区 生物学 Q1 MICROBIOLOGY mBio Pub Date : 2024-10-30 DOI:10.1128/mbio.01699-24
Ana J Choi, Daniel J Bennison, Esha Kulkarni, Hibah Azar, Haoyu Sun, Hanqi Li, Jonathan Bradshaw, Hui Wen Yeap, Nicholas Lim, Vishwas Mishra, Anna Crespo-Puig, Ewurabena A Mills, Frances Davies, Shiranee Sriskandan, Avinash R Shenoy
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Abstract

Enterobacter cloacae is a Gram-negative nosocomial pathogen of the ESKAPE (Enterococcus, Staphylococcus, Klebsiella, Acinetobacter, Pseudomonas, and Enterobacter spp.) priority group with increasing multi-drug resistance via the acquisition of resistance plasmids. However, E. cloacae can also display forms of antibiotic refractoriness, such as heteroresistance and tolerance. Here, we report that E. cloacae displays transient heteroresistance to aminoglycosides, which is accompanied with the formation of small colony variants (SCVs) with increased minimum inhibitor concentration (MIC) of gentamicin and other aminoglycosides used in the clinic, but not other antibiotic classes. To explore the underlying mechanisms, we performed RNA sequencing of heteroresistant bacteria, which revealed global gene expression changes and a signature of the CpxRA cell envelope stress response. Deletion of the cpxRA two-component system abrogated aminoglycoside heteroresistance and SCV formation, pointing to its indispensable role in these processes. The introduction of a constitutively active allele of cpxA led to high aminoglycoside MICs, consistent with cell envelope stress response driving these behaviors in E. cloacae. Cell envelope stress can be caused by environmental cues, including heavy metals. Indeed, bacterial exposure to copper increased gentamicin MIC in the wild-type but not in the ΔcpxRA mutant. Moreover, copper exposure also elevated the gentamicin MICs of clinical isolates from bloodstream infections, suggesting that CpxRA- and copper-dependent aminoglycoside resistance is broadly conserved in E. cloacae strains. Altogether, we establish that E. cloacae relies on transcriptional reprogramming via the envelope stress response pathway for transient resistance to a major class of frontline antibiotic.IMPORTANCEEnterobacter cloacae is a bacterium that belongs to the WHO high-priority group and an increasing threat worldwide due its multi-drug resistance. E. cloacae can also display heteroresistance, which has been linked to treatment failure. We report that E. cloacae shows heteroresistance to aminoglycoside antibiotics. These are important frontline microbicidal drugs used against Gram-negative bacterial infections; therefore, understanding how resistance develops among sensitive strains is important. We show that aminoglycoside resistance is driven by the activation of the cell envelope stress response and transcriptional reprogramming via the CpxRA two-component system. Furthermore, heterologous activation of envelope stress via copper, typically a heavy metal with antimicrobial actions, also increased aminoglycoside MICs of the E. cloacae type strain and clinical strains isolated from bloodstream infections. Our study suggests aminoglycoside recalcitrance in E. cloacae could be broadly conserved and cautions against the undesirable effects of copper.

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泄殖腔肠杆菌对氨基糖苷类药物的异抗性是由细胞膜应激反应驱动的。
泄殖腔肠杆菌是 ESKAPE(肠球菌属、葡萄球菌属、克雷伯氏菌属、不动杆菌属、假单胞菌属和肠杆菌属)优先类群中的一种革兰氏阴性医院病原体,通过获得抗性质粒而产生越来越强的多重耐药性。然而,泄殖腔杆菌也会表现出各种形式的抗生素耐药性,如异抗性和耐受性。在此,我们报告了泄殖腔杆菌对氨基糖苷类药物表现出的短暂异抗性,这种异抗性伴随着小菌落变异体(SCVs)的形成,其对庆大霉素和其他临床使用的氨基糖苷类药物的最小抑菌浓度(MIC)有所提高,但对其他抗生素类药物的最小抑菌浓度(MIC)却没有提高。为了探索其潜在机制,我们对异抗性细菌进行了 RNA 测序,结果发现了全基因表达的变化和 CpxRA 细胞膜应激反应的特征。删除 cpxRA 双组分系统可消除氨基糖苷类异抗性和 SCV 的形成,这表明它在这些过程中起着不可或缺的作用。引入 cpxA 的组成型活性等位基因会导致氨基糖苷类药物的高 MIC,这与衣藻中驱动这些行为的细胞包膜应激反应是一致的。包括重金属在内的环境线索可导致细胞包膜应激反应。事实上,细菌暴露于铜会增加野生型的庆大霉素 MIC,但不会增加 ΔcpxRA 突变体的 MIC。此外,铜暴露也会提高来自血液感染的临床分离株的庆大霉素 MIC,这表明 CpxRA 和铜依赖性氨基糖苷类耐药性在泄殖腔杆菌菌株中广泛存在。总之,我们确定泄殖腔杆菌依赖于通过包膜应激反应途径进行转录重编程,从而对一类主要的一线抗生素产生瞬时耐药性。 重要意义泄殖腔杆菌是一种属于世界卫生组织高危细菌群的细菌,由于其具有多重耐药性,对全球的威胁日益严重。泄殖腔杆菌还可表现出异抗性,这与治疗失败有关。我们报告了泄殖腔杆菌对氨基糖苷类抗生素的异抗性。氨基糖苷类抗生素是治疗革兰氏阴性细菌感染的重要一线杀菌药物;因此,了解敏感菌株的耐药性是非常重要的。我们的研究表明,氨基糖苷类药物的耐药性是通过 CpxRA 双组分系统激活细胞包膜应激反应和转录重编程驱动的。此外,通过铜(一种典型的具有抗菌作用的重金属)异源激活包膜应激反应,也会增加泄殖腔大肠杆菌型菌株和从血液感染中分离出的临床菌株的氨基糖苷类药物 MIC。我们的研究表明,泄殖腔杆菌对氨基糖苷类药物的不耐受性可能具有广泛的保守性,并提醒人们注意铜的不良影响。
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来源期刊
mBio
mBio MICROBIOLOGY-
CiteScore
10.50
自引率
3.10%
发文量
762
审稿时长
1 months
期刊介绍: mBio® is ASM''s first broad-scope, online-only, open access journal. mBio offers streamlined review and publication of the best research in microbiology and allied fields.
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