Revisiting unexploited antibiotics in search of new antibacterial drug candidates: the case of MSD-819 (6-chloro-2-quinoxalinecarboxylic acid 1,4-dioxide).
Revisiting unexploited antibiotics in search of new antibacterial drug candidates: the case of MSD-819 (6-chloro-2-quinoxalinecarboxylic acid 1,4-dioxide).
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重新审视未开发的抗生素以寻找新的抗菌药物候选物：以 MSD-819（6-氯-2-喹喔啉甲酸 1,4-二氧化物）为例。
DOI：
10.1038/ja.2016.140
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发表时间：
2017
期刊：
影响因子：
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通讯作者：
Ooi N
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文献类型：
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作者：
Ooi N
细菌病原体中抗生素耐药性的出现和传播正在极大地破坏我们治疗感染的能力，引发公共卫生危机。1 ESKAPE病原体（屎肠球菌、金黄色葡萄球菌、肺炎克雷伯菌、鲍曼不动杆菌、铜绿假单胞菌和肠杆菌属）引起的感染情况尤其严重，2，3这是一组名称反映其能够“逃避”现有抗菌药物作用的微生物。虽然这些病原体带来的问题可以通过开发对它们有活性的新型抗菌剂来有效解决，但事实证明，说起来容易做起来难;抗菌药物发现领域现已进入“发现空白”30年，在此期间没有新的类别解决ESKAPE病原体已成功从发现进展到临床。4一种鉴定新的抗菌药物候选物的方法涉及重新审视尚未用于治疗细菌性疾病的已知天然产物抗生素。大量的此类化合物存在，因为C。到目前为止，已经发现了3000种抗生素，只有少数几类抗生素被开发用于临床。5在这些未开发的抗生素中，特别令人感兴趣的是那些已经被证明具有潜在抗菌药物所需的特性以解决ESKAPE病原体引起的感染的抗生素，例如，广谱活性和在动物模型中证明的抗菌功效。虽然这些化合物中的一部分可能会被考虑并拒绝开发，因为它们具有科学文献中未报道的责任，但也可以想象，许多化合物没有被严格评估为候选药物。此外，有几种抗生素最初被视为候选药物，但后来被重新审视并成功开发用于临床使用（例如，达托霉素，非达霉素，截短侧耳素）。因此，我们认为对已知的天然产物抗生素进行大规模的重新评估以确定抗菌药物候选物是一项值得努力的奋进。然而，为了纠正过去抗菌药物发现工作的不透明性，并防止未来的重复努力，我们认为科学记录全面捕获以下两方面的细节至关重要：
The emergence and spread of antibiotic resistance in bacterial pathogens is dramatically undermining our ability to treat infection, precipitating a public health crisis. 1 The situation is particularly grave in the case of infections caused by the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species), 2, 3 a group of organisms whose name reflects their ability to ‘escape’the action of existing antibacterial drugs. While the problem presented by these pathogens could be effectively addressed by developing novel antibacterial agents active against them, this is proving easier said than done; the field of antibacterial drug discovery is now 30 years into a ‘Discovery Void’, a period during which no new classes addressing the ESKAPE pathogens have successfully progressed from discovery to clinic. 4One approach to identifying new antibacterial drug candidates involves revisiting known natural product antibiotics that have not been exploited for treating bacterial disease. A wealth of such compounds exist, since of the c. 3000 antibiotics discovered to date, only a handful of classes have been developed for clinical use. 5 Of particular interest amongst these unexploited antibiotics are those that have already been documented to possess properties desirable in a potential antibacterial drug to tackle infections caused by the ESKAPE pathogens, for example, broad-spectrum activity and demonstrated antibacterial efficacy in animal models. While a proportion of such compounds will likely have been considered and rejected for development because they possess liabilities that went unreported in the scientific literature, it is also conceivable that many have not been rigorously evaluated as drug candidates. Furthermore, there are several examples of antibiotics that were initially dismissed as drug candidates, but were later revisited and successfully developed for clinical use (for example, daptomycin, fidaxomicin, pleuromutilins). 4 Thus, we consider a large-scale re-evaluation of known natural product antibiotics to identify antibacterial drug candidates to be a worthwhile endeavor. However, to redress the opacity of past antibacterial drug discovery efforts 4 and to prevent future duplication of effort, we consider it vital that the scientific record comprehensively captures the details both for