ArmR: a novel drug target and mediator of antibiotic resistance

耐药的革兰氏阴性细菌是医院获得性疾病的一个日益增加的原因 感染、死亡率和医疗费用的巨大负担。鲍曼不动杆菌是一种 最近出现了这种感染的主要原因和菌株，它们甚至对 最后一道防线药物，多粘菌素B和粘菌素(多粘菌素E)，它们靶向和破坏 脂类：外膜中脂多糖的一部分。了解 这种抗性在分子水平上的机制将促进新品种的发展 治疗的目的是逆转耐药性，其方式与β-内酰胺酶大致相同 抑制剂可以抵消青霉素耐药性。为此，我们最近确定了一部小说 我们已经命名为ARMR(或ARMAR-通过脂质修饰产生的抗菌素耐药性)的蛋白质 一种表面电荷)，它是广泛守恒的，我们证明它是抵抗 鲍曼不动杆菌和其他革兰氏阴性菌中的多粘菌素。需要ARMR才能 脂类：一种导致细菌膜表面电荷增加的修饰。 作用于排斥带正电的多粘菌素以及带正电的宿主衍生的 抗菌肽。我们假设，对ARMR的抑制将逆转对 多粘菌素，保留其在临床上的效用，并使细菌对先天宿主敏感 防御。

Drug resistant Gram-negative bacterial pathogens are an increasing cause of hospital-acquired infections, mortality, and a huge burden on healthcare costs. Acinetobacter baumannii is a major cause of such infections and strains have recently emerged which are resistant even to the last line of defense drugs, polymyxin B and colistin (polymyxin E), which target and disrupt the lipid A portion of lipopolysaccharide (LPS) in the outer membrane. Understanding the mechanism of this resistance at the molecular level would facilitate the development of novel therapeutics aimed at reversing resistance, in much the same way that beta-lactamase inhibitors can counteract penicillin resistance. To this end, we have recently identified a novel protein that we have named ArmR (or Armor - Antimicrobial Resistance by Modification of lipid A surface chaRge) that is widely conserved and which we show is required for resistance to polymyxins in A. baumannii as well as other Gram-negative bacteria. ArmR is required for a lipid A modification that leads to the increase of surface charge on the bacterial membrane, acting to repel the positively charged polymyxins as well as positively charged host-derived antimicrobial peptides. We hypothesize that inhibition of ArmR would reverse the resistance to polymyxins, preserving their utility in the clinic, and also sensitize the bacteria to innate host defenses.