A New Nucleoside Antibiotic Chokes Bacterial RNA Polymerase.
A New Nucleoside Antibiotic Chokes Bacterial RNA Polymerase.
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一种新型核苷抗生素可抑制细菌 RNA 聚合酶。
DOI：
10.1021/acs.biochem.7b00680
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发表时间：
2017
期刊：
影响因子：
2.9
通讯作者：
Crawford,JasonM
中科院分区：
文献类型：
--
作者：
Trautman,EricP;Crawford,JasonM
最近发现的第一个细菌RNA聚合酶（RNAP）的核苷类似物抑制剂在对抗耐药细菌的军备竞赛中引入了一种新武器。1.细菌多重耐药性的传播速度超过了新抗生素进入临床的速度。以前的最后一道防线疗法，如万古霉素，正在失去疗效，因为随着抗生素的使用，耐药菌株的流行率增加。因此，细菌导致的死亡人数呈上升趋势，仅在美国每年就有至少2.3万人死于耐药感染。虽然抗生素耐药性一直在上升，但由于多种原因，对新抗生素的研究已经放缓。由于即将到来的健康危机，发现新的抗生素，特别是那些具有新作用机制的抗生素，是对抗耐药感染的关键。Mackoli等人描述了假尿嘧啶霉素的表征，假尿嘧啶霉素是革兰氏阳性和革兰氏阴性生物体中靶向细菌RNAP的第一种核苷类似物抗生素。1该抗生素是从包含在3000个成员的放线菌提取物文库中的两个链霉菌生产者中鉴定的。对该文库进行了体外细菌和病毒RNAP抑制活性检查，重点是发现选择性细菌抑制剂。虽然其他抗生素，如利福平，靶向细菌RNAP，这种分子靶向活性位点，并直接与核苷酸底物竞争，如通过分子和RNAP的共晶结构，耐药性突变的检查，以及从一系列相关的体外生物化学测定结果的解释。作者表明，由于不同的作用机制，耐药性细菌，如耐甲氧西林金黄色葡萄球菌（MRSA）菌株，对这种新抗生素敏感，并且在他们的实验条件下，对假脲霉素的耐药性自发发展率比利福平低一个数量级。这种较低的突变率可能是由于底物和抑制剂之间的相似性，这减少了可能保留功能同时减弱蛋白质对抑制剂的亲和力的可能突变的数量。此外，由于靶点是中心酶，因此假尿嘧啶霉素预期具有广谱功效。假尿嘧啶霉素显示出作为潜在的小分子药物先导的前景。核苷类似物抑制剂已被公认为优秀的候选药物，并在治疗病毒性疾病如肝炎和HIV方面取得了巨大成功。Harvoni是一种治疗丙型肝炎的药物，是2016年第二高的药物，是两种药物的联合治疗，其中一种是核苷类似物。第一个引入的HIV治疗也是核苷类似物，叠氮胸苷，核苷类似物至今仍是治疗HIV的联合治疗的主要组成部分。从机制上讲，这些成功的分子抑制病毒聚合酶或逆转录酶，同时对人RNAP具有较低水平的脱靶抑制。类似地，假尿嘧啶霉素抑制细菌RNAP，同时对人RNAP具有较低的效力。Minguloli等人1表明，在体外试验中，假尿嘧啶霉素对细菌细胞系的效力比对人细胞的效力高约6 - 60倍。小鼠模型实验进一步扩展了这些有希望的结果，表明假尿嘧啶霉素可以成功地治疗
The recent discovery of the first nucleoside analogue inhibitor of bacterial RNA polymerase (RNAP) introduces a new weapon in the arms race against drug-resistant bacteria. 1 The spread of multidrug resistance among bacteria has outpaced the introduction of new antibiotics into the clinic. Previous last-line-of-defense therapies, such as vancomycin, are losing efficacy as the prevalence of drug-resistant isolates increases with antibiotic use. As a result, the number of deaths caused by bacteria is on the rise, with at least 23000 people dying from drug-resistant infections each year in the United States alone. While antibiotic resistance has been rising, research into new antibiotics has slowed for a multitude of reasons. Because of the impending heath crisis, the discovery of new antibiotics, particularly those with novel mechanisms of action, is key to combating drug-resistant infections. Maffioli et al. describe the characterization of pseudouridimycin, the first nucleoside analogue antibiotic that targets bacterial RNAP in Gram-positive and Gram-negative organisms. 1 The antibiotic was identified from two Streptomyces producers included within a 3000-member actinobacterial extract library. This library was examined for in vitro bacterial and viral RNAP inhibitory activities with a focus on discovering selective bacterial inhibitors. While other antibiotics, such as rifampin, target bacterial RNAP, this molecule targets the active site and directly competes with nucleotide substrates, as assessed by cocrystal structures of the molecule and RNAP, examination of resistance mutations, and interpretation of the results from a series of associated in vitro biochemical assays. The authors show, as a result of the differential mechanisms of action, that antibiotic-resistant bacteria, such as strains of methicillinresistant Staphylococcus aureus (MRSA), are susceptible to this new antibiotic and the rate of spontaneous development of resistance to pseudouridimycin is an order of magnitude lower than that of rifampin under the conditions of their experiments. This lower mutation rate is likely due to the similarity between the substrate and inhibitor, which reduces the number of possible mutations that could retain function while attenuating the affinity of the protein for the inhibitor. Additionally, as the target is a central enzyme, pseudouridimycin is expected to have broad-spectrum efficacy. Pseudouridimycin shows promise as a potential small molecule drug lead. Nucleoside analogue inhibitors have been recognized as excellent drug candidates and have found enormous success in the treatment of viral diseases such as hepatitis and HIV. Harvoni, a cure for hepatitis C, was the second highest grossing drug in 2016 and is a combination therapy of two drugs, one being a nucleoside analogue. The first HIV treatment to be introduced was also a nucleoside analogue, azidothymidine, and nucleoside analogues are still a major component of combination therapy in treating HIV to this day. Mechanistically, these successful molecules inhibit viral polymerases or reverse transcriptases, while having a lower level of off-target inhibition of human RNAPs. Similarly, pseudouridimycin inhibits bacterial RNAP while having a lower potency against human RNAP. Maffioli et al. 1 show that in in vitro assays, the potency of pseudouridimycin is approximately 6− 60 times higher for bacterial cell lines than for human cells. Mouse model experiments extend these promising results one step further, showing that pseudouridimycin can successfully treat a