Chen Annie I, Albicoro Francisco Javier, Zhu Jun, Goulian Mark
Cell and Molecular Biology Graduate Group, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Antimicrob Agents Chemother. 2021 Feb 17;65(3). doi: 10.1128/AAC.00889-20.
Polymyxins are a class of cyclic peptides with antimicrobial activity against Gram-negative bacteria. In , the PhoQ/PhoP and PmrB/PmrA two-component systems regulate many genes that confer resistance to both polymyxins and host antimicrobial peptides. The activities of these two-component systems are modulated by additional proteins that are conserved across , such as MgrB, a negative regulator of PhoQ, and PmrD, a "connector" protein that activates PmrB/PmrA in response to PhoQ/PhoP stimulation. Despite the conservation of many protein components of the PhoQ/PhoP-PmrD-PmrB/PmrA network, the specific molecular interactions and regulatory mechanisms vary across different genera. Here, we explore the role of PmrD in modulating this signaling network in and We show that in , PmrD is not required for polymyxin resistance arising from mutation of -the most common cause of spontaneous polymyxin resistance in this bacterium-suggesting that direct activation of polymyxin resistance genes by PhoQ/PhoP plays a critical role in this resistance pathway. However, for conditions of low pH or intermediate iron concentrations, both of which stimulate PmrB/PmrA, we find that PmrD does contribute to resistance. We further show that in , PmrD functions as a connector between PhoQ/PhoP and PmrB/PmrA, in contrast with previous reports. In this case, activity also depends on PmrB/PmrA stimulation, or on very high activation of PhoQ/PhoP. Our results indicate that the importance of the PmrD connector in modulating the polymyxin resistance network depends on both the network organization and on the environmental conditions associated with PmrB stimulation.
多粘菌素是一类对革兰氏阴性菌具有抗菌活性的环肽。在[具体细菌名称]中，PhoQ/PhoP和PmrB/PmrA双组分系统调控许多赋予对多粘菌素和宿主抗菌肽抗性的基因。这些双组分系统的活性由在[具体范围]中保守的其他蛋白质调节，例如PhoQ的负调节因子MgrB和响应PhoQ/PhoP刺激激活PmrB/PmrA的“连接”蛋白PmrD。尽管PhoQ/PhoP - PmrD - PmrB/PmrA网络的许多蛋白质组分具有保守性，但具体的分子相互作用和调控机制在不同属之间有所不同。在这里，我们探究PmrD在[具体细菌名称1]和[具体细菌名称2]中调节该信号网络的作用。我们表明，在[具体细菌名称1]中，由[具体基因名称]突变引起的多粘菌素抗性（该细菌中自发多粘菌素抗性的最常见原因）并不需要PmrD，这表明PhoQ/PhoP直接激活多粘菌素抗性基因在该抗性途径中起关键作用。然而，对于低pH或中等铁浓度条件（这两种条件均刺激PmrB/PmrA），我们发现PmrD确实有助于抗性。我们进一步表明，与之前的报道相反，在[具体细菌名称2]中，PmrD作为PhoQ/PhoP和PmrB/PmrA之间的连接蛋白发挥作用。在这种情况下，活性也取决于PmrB/PmrA刺激或PhoQ/PhoP的非常高的激活。我们的结果表明，PmrD连接蛋白在调节多粘菌素抗性网络中的重要性取决于网络组织以及与PmrB刺激相关的环境条件。
