Department of Biology, University of Texas at Arlington, Arlington, TX, USA.
Department of Chemistry, University of Texas at Austin, Austin, TX, USA.
Mol Microbiol. 2019 Jun;111(6):1604-1616. doi: 10.1111/mmi.14240. Epub 2019 Apr 10.
The Enterobacter cloacae complex (ECC) consists of closely related bacteria commonly associated with the human microbiota. ECC are increasingly isolated from healthcare-associated infections, demonstrating that these Enterobacteriaceae are emerging nosocomial pathogens. ECC can rapidly acquire multidrug resistance to conventional antibiotics. Cationic antimicrobial peptides (CAMPs) have served as therapeutic alternatives because they target the highly conserved lipid A component of the Gram-negative outer membrane. Many Enterobacteriaceae fortify their outer membrane with cationic amine-containing moieties to prevent CAMP binding, which can lead to cell lysis. The PmrAB two-component system (TCS) directly activates 4-amino-4-deoxy-l-arabinose (l-Ara4N) biosynthesis to result in cationic amine moiety addition to lipid A in many Enterobacteriaceae such as E. coli and Salmonella. In contrast, PmrAB is dispensable for CAMP resistance in E. cloacae. Interestingly, some ECC clusters exhibit colistin heteroresistance, where a subpopulation of cells exhibit clinically significant resistance levels compared to the majority population. We demonstrate that E. cloacae lipid A is modified with l-Ara4N to induce CAMP heteroresistance and the regulatory mechanism is independent of the PmrAB TCS. Instead, PhoP binds to the arnB promoter to induce l-Ara4N biosynthesis and PmrAB-independent addition to the lipid A disaccharolipid. Therefore, PhoPQ contributes to regulation of CAMP heteroresistance in some ECC clusters.
阴沟肠杆菌复合体（ECC）由与人类微生物群密切相关的密切相关的细菌组成。ECC 越来越多地从与医疗保健相关的感染中分离出来，这表明这些肠杆菌科是新兴的医院病原体。ECC 可以迅速获得对传统抗生素的多药耐药性。阳离子抗菌肽（CAMPs）已被用作治疗替代品，因为它们针对革兰氏阴性外膜的高度保守脂质 A 成分。许多肠杆菌科用含阳离子胺的部分强化其外膜，以防止 CAMP 结合，这可能导致细胞裂解。PmrAB 双组分系统（TCS）直接激活 4-氨基-4-脱氧-l-阿拉伯糖（l-Ara4N）的生物合成，导致许多肠杆菌科（如大肠杆菌和沙门氏菌）的脂质 A 中添加阳离子胺部分。相比之下，PmrAB 对于阴沟肠杆菌的 CAMP 抗性是可有可无的。有趣的是，一些 ECC 簇表现出多粘菌素异质性耐药性，其中一部分细胞与大多数细胞相比表现出临床显著的耐药水平。我们证明阴沟肠杆菌的脂质 A 用 l-Ara4N 修饰以诱导 CAMP 异质性耐药性，并且调节机制独立于 PmrAB TCS。相反，PhoP 结合到 arnB 启动子以诱导 l-Ara4N 的生物合成和 PmrAB 独立地添加到脂质 A 二糖脂。因此，PhoPQ 有助于一些 ECC 簇中 CAMP 异质性耐药性的调节。
