ArmR: a novel drug target and mediator of antibiotic resistance

描述（由申请人提供）：耐药革兰氏阴性细菌病原体是医院获得性感染、死亡率和医疗保健费用的巨大负担的日益增加的原因。鲍氏不动杆菌是这种感染的主要原因，并且最近出现了甚至对“最后一道防线”药物多粘菌素B和粘菌素（多粘菌素E）具有抗性的菌株，所述药物靶向并破坏鲍氏不动杆菌中脂多糖（LPS）的脂质A部分。 外膜。在分子水平上理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，我们最近鉴定了一种新的蛋白质，我们将其命名为ArmR（或“Armor”-通过修饰脂质A表面电荷的抗微生物抗性），该蛋白质是广泛保守的，并且我们表明其是A中对多粘菌素的抗性所必需的。鲍曼不动杆菌以及其它革兰氏阴性菌。ArmR是脂质A修饰所必需的，脂质A修饰导致细菌膜上的表面电荷增加，从而起到排斥带正电荷的多粘菌素以及带正电荷的宿主衍生的抗微生物肽的作用。我们假设，抑制ArmR将逆转对多粘菌素的耐药性，保留其在临床中的效用，并且还使细菌对先天宿主防御敏感。 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卫生保健问题。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。由于此处靶向的“耐药蛋白”广泛保守并存在于其他耐药细菌中，因此这项工作可能导致一种新型广谱抗生素，以对抗最广泛的耐药革兰氏阴性病原体。

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.