Antibacterial Discovery: 21st Century Challenges
Antibacterial Discovery: 21st Century Challenges
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DOI：
10.3390/antibiotics9050213
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发表时间：
2020-05-01
影响因子：
4.8
通讯作者：
Hoffman, Paul S.
中科院分区：
文献类型：
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作者：
Hoffman, Paul S.
自抗生素发现的黄金时代（1945-1975）结束以来已经过去了近50年;然而，我们仍然在努力确定新的药物靶点，并提供新的化学抗生素类别，以取代那些因耐药性而过时的抗生素。尽管利用广泛的抗生素发现平台策略（包括基因组学、生物信息学、系统生物学和后基因组方法）做出了巨大的努力，但成功充其量只是渐进的。显然，发现新的抗生素种类真的很难，所以重复旧的策略，同时期待不同的结果，似乎接近疯狂。本综述涉及的关键问题包括：（1）如果基于突变的耐药性是任何新抗生素的主要挑战，那么是否有可能找到能够避免这种结果的药物靶标和新的化学实体：（2）新的抗菌药物化学类别的数量是否受到广谱药物靶标数量的限制;（3）如果这是真的，那么我们是否应该把精力集中在病原体的亚群上，如革兰氏阴性或阳性细菌，厌氧菌或其他群体，其中共同的必需基因的范围可能更大？该综述还提供了一些现有药物靶点的例子，这些靶点似乎逃脱了基于突变的耐药性的幽灵，并提供了一些中间谱策略以及现代分子和基因组方法的例子，这些策略以及现代分子和基因组方法可能会提高提供21世纪药物以对抗多药耐药病原体的几率。
It has been nearly 50 years since the golden age of antibiotic discovery (1945-1975) ended; yet, we still struggle to identify novel drug targets and to deliver new chemical classes of antibiotics to replace those rendered obsolete by drug resistance. Despite herculean efforts utilizing a wide range of antibiotic discovery platform strategies, including genomics, bioinformatics, systems biology and postgenomic approaches, success has been at best incremental. Obviously, finding new classes of antibiotics is really hard, so repeating the old strategies, while expecting different outcomes, seems to boarder on insanity. The key questions dealt with in this review include: (1) If mutation based drug resistance is the major challenge to any new antibiotic, is it possible to find drug targets and new chemical entities that can escape this outcome; (2) Is the number of novel chemical classes of antibacterials limited by the number of broad spectrum drug targets; and (3) If true, then should we focus efforts on subgroups of pathogens like Gram negative or positive bacteria only, anaerobic bacteria or other group where the range of common essential genes is likely greater?. This review also provides some examples of existing drug targets that appear to escape the specter of mutation based drug resistance, and provides examples of some intermediate spectrum strategies as well as modern molecular and genomic approaches likely to improve the odds of delivering 21st century medicines to combat multidrug resistant pathogens.