Abstract

Dr. Vladimir Skulachev was my mentor, and his pioneering work in the field of bioenergetics inspired the discoveries described in this review, written in the form of a personal account of events. Examining basic mechanisms of chemiosmotic coupling unexpectedly led us to transenvelope multidrug resistance pumps (MDR pumps) that severely limit development of novel antibiotics. One of the major advances of Skulachev and his group was the discovery of the mitochondrial membrane potential with the use of permeant cations such as TPP⁺, which served as electric probes. We describe our finding of their natural counterparts in plants, where they act as antimicrobials. The most challenging problems in antimicrobial drug discovery are antibiotic tolerance of chronic infections caused by dormant persister cells; antibiotic resistance, responsible for the current antimicrobial resistance crisis (AMR); and finding novel compounds acting against Gram-negative bacteria, protected by their powerful multidrug resistance pumps. Our study of persisters shows that these are rare cells formed by stochastic fluctuation in expression of Krebs cycle enzymes, leading to a drop in ATP, target shutdown, and antibiotic tolerance. Searching for compounds that can corrupt targets in the absence of ATP, we identified acyldepsipeptide (ADEP) that activates the ClpP protease, forcing cells to self-digest. Growing previously uncultured bacteria led us to teixobactin, a novel cell wall acting antibiotic. Teixobactin avoids efflux by targeting lipid II and lipid III, precursors of peptidoglycan and wall teichoic acid, located on the surface. The targets are immutable, and teixobactin is the first antibiotic with no detectable resistance. Our search for compounds acting against Gram-negative bacteria led to the discovery of darobactins, which also hit a surface target, the essential chaperone BamA.

中文翻译：

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在生物能学和抗生素发现的十字路口

摘要

弗拉基米尔·斯库拉切夫（Vladimir Skulachev）博士是我的导师，他在生物能学领域的开创性工作激发了本评论中所描述的发现，这些发现是以事件的个人陈述形式撰写的。检查化学渗透耦合的基本机制出乎意料地导致我们开发出跨信封的多药耐药泵（MDR泵），该泵严重限制了新型抗生素的开发。Skulachev及其小组的主要进步之一是利用渗透性阳离子（如TPP ^+）发现了线粒体膜的潜力。，用作电探针。我们描述了它们在植物中作为抗菌剂的天然对应物的发现。抗菌药物发现中最具挑战性的问题是对休眠性持久性细胞引起的慢性感染的抗生素耐受性。抗生素耐药性，造成当前的抗菌素耐药性危机（AMR）；并找到可抵抗革兰氏阴性细菌的新型化合物，并受到其强大的耐多药泵的保护。我们对持久性的研究表明，这些细胞是由Krebs循环酶表达的随机波动形成的稀有细胞，导致ATP下降，靶点关闭和抗生素耐受性下降。在没有ATP的情况下，寻找可以破坏靶标的化合物，我们鉴定了能激活ClpP蛋白酶，迫使细胞自我消化的酰基肽肽（ADEP）。以前未培养的细菌的生长使我们产生了teixobactin，一种新型的细胞壁作用抗生素。Teixobactin通过靶向位于表面的脂质II和脂质III（肽聚糖的前体和壁壁chochochoic acid）避免外排。目标是一成不变的，teixobactin是第一种没有可检测的耐药性的抗生素。我们寻找可对抗革兰氏阴性细菌的化合物的结果，导致了darobactins的发现，而darobactins也命中了一个表面靶标，即必需的伴侣BamA。