ArmR: a novel drug target and mediator of antibiotic resistance

描述(申请人提供)：耐药革兰氏阴性细菌病原体是医院获得性感染、死亡率和医疗费用的巨大负担的日益增长的原因。鲍曼不动杆菌是引起这种感染的主要原因，最近出现的菌株甚至对“最后一道防线”药物--多粘菌素B和粘菌素(多粘菌素E)也具有抗药性，这些药物靶向并破坏脂多糖(LPS)的脂A部分。 外膜。在分子水平上了解这种耐药性的机制将有助于开发旨在逆转耐药性的新疗法，就像β-内酰胺酶抑制剂可以抵消青霉素耐药性一样。为此，我们最近发现了一种新的蛋白质，我们将其命名为Armr(或“Armor”-通过修饰脂质A表面电荷产生的抗菌素耐药性)，它是广泛保守的，我们证明了它是鲍曼不动杆菌和其他革兰氏阴性细菌对多粘菌素耐药所必需的。ARMR是脂质A修饰所必需的，这种修饰导致细菌膜上表面电荷的增加，从而排斥带正电的多粘蛋白以及带正电的宿主衍生的抗菌肽。我们假设，抑制ARMR将逆转对多粘菌素的耐药性，保留它们在临床上的效用，并使细菌对固有的宿主防御系统敏感。 公共卫生相关性：革兰氏阴性细菌病原体对抗生素的耐药性是一个日益严重的医疗保健问题。本研究的目的是更好地了解鲍曼不动杆菌对“最后一线”抗生素的耐药机制，并开发治疗此类感染的新药。由于这里针对的“耐药蛋白”广泛保守，并存在于其他耐药细菌中，这项工作可能会导致一种新的广谱抗生素来对抗最广泛耐药的革兰氏阴性病原体。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Resistance of Gram-negative bacterial pathogens to antibiotics is an increasing and severe healthcare problem. The aim of this research is to better understand the mechanism of Acinetobacter baumannii resistance to "last line" antibiotics, and to develop new drugs to treat such infections. Since the "resistance protein" targeted here is widely conserved and present in other drug-resistant bacteria, this work may lead to a novel broad-spectrum antibiotic to combat the most extensively drug-resistant Gram-negative pathogens.