Laboratory Microbial Pathogenesis, Fundació d'Investigació Sanitària de les Illes Balears, Recinto Hospital Joan March, Carretera Soller Km 12, 07110 Bunyola, Spain.
Infect Immun. 2011 Sep;79(9):3718-32. doi: 10.1128/IAI.05226-11. Epub 2011 Jun 27.
Antimicrobial peptides (APs) impose a threat to the survival of pathogens, and it is reasonable to postulate that bacteria have developed strategies to counteract them. Polymyxins are becoming the last resort to treat infections caused by multidrug-resistant Gram-negative bacteria and, similar to APs, they interact with the anionic lipopolysaccharide. Given that polymyxins and APs share the initial target, it is possible that bacterial defense mechanisms against polymyxins will be also effective against host APs. We sought to determine whether exposure to polymyxin will increase Klebsiella pneumoniae resistance to host APs. Indeed, exposure of K. pneumoniae to polymyxin induces cross-resistance not only to polymyxin itself but also to APs present in the airways. Polymyxin treatment upregulates the expression of the capsule polysaccharide operon and the loci required to modify the lipid A with aminoarabinose and palmitate with a concomitant increase in capsule and lipid A species containing such modifications. Moreover, these surface changes contribute to APs resistance and also to polymyxin-induced cross-resistance to APs. Bacterial loads of lipid A mutants in trachea and lungs of intranasally infected mice were lower than those of wild-type strain. PhoPQ, PmrAB, and the Rcs system govern polymyxin-induced transcriptional changes, and there is a cross talk between PhoPQ and the Rcs system. Our findings support the notion that Klebsiella activates a defense program against APs that is controlled by three signaling systems. Therapeutic strategies directed to prevent the activation of this program could be a new approach worth exploring to facilitate the clearance of the pathogen from the airways.
抗菌肽 (APs) 对病原体的生存构成威胁，因此可以合理地假设细菌已经开发出了对抗它们的策略。多黏菌素类药物正成为治疗多重耐药革兰氏阴性菌感染的最后手段，与 APs 类似，它们与阴离子脂多糖相互作用。鉴于多黏菌素类药物和 APs 具有共同的初始靶标，针对多黏菌素类药物的细菌防御机制可能也对宿主 APs 有效。我们试图确定暴露于多黏菌素类药物是否会增加肺炎克雷伯菌对宿主 APs 的耐药性。事实上，肺炎克雷伯菌暴露于多黏菌素类药物不仅会导致对多黏菌素类药物本身的交叉耐药性，还会导致对气道中存在的 APs 的交叉耐药性。多黏菌素类药物处理上调了荚膜多糖操纵子的表达，以及用氨基阿拉伯糖和棕榈酸修饰脂 A 所需的基因座，同时增加了含有这些修饰的荚膜和脂 A 种类。此外，这些表面变化有助于 APs 耐药性以及多黏菌素类药物诱导的对 APs 的交叉耐药性。与野生型菌株相比，经鼻腔感染小鼠气管和肺部的脂 A 突变体的细菌负荷较低。PhoPQ、PmrAB 和 Rcs 系统控制多黏菌素类药物诱导的转录变化，PhoPQ 和 Rcs 系统之间存在交叉对话。我们的研究结果支持这样一种观点，即肺炎克雷伯菌激活了一种针对 APs 的防御程序，该程序由三个信号系统控制。针对防止该程序激活的治疗策略可能是一种值得探索的新方法，有助于清除气道中的病原体。
