Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37240, United States.
Department of Biological Sciences, Vanderbilt University, Nashville, Tennessee 37232, United States.
Biochemistry. 2024 Nov 5;63(21):2705-2713. doi: 10.1021/acs.biochem.4c00464. Epub 2024 Oct 15.
Antibiotics are essential components of current medical practice, but their effectiveness is being eroded by the increasing emergence of antimicrobial-resistant infections. At the same time, the rate of antibiotic discovery has slowed, and our future ability to treat infections is threatened. Among Christopher T. Walsh's many contributions to science was his early recognition of this threat and the potential of biosynthesis─genes and mechanisms─to contribute solutions. Here, we revisit a 2006 review by Walsh and co-workers that highlighted a major challenge in antibiotic natural product discovery: the daunting odds for identifying new naturally occurring antibiotics. The review described strategies to mitigate the odds challenge. These strategies have been used extensively by the natural product discovery community in the years since and have resulted in some promising discoveries. Despite these advances, the rarity of novel antibiotic natural products remains a barrier to discovery. We compare the challenge of discovering natural product antibiotics to the process of identifying new prime numbers, which are also challenging to find and an essential, if underappreciated, element of modern life. We propose that inclusion of filters for functional compounds early in the discovery pipeline is key to natural product antibiotic discovery, review some recent advances that enable this, and discuss some remaining challenges that need to be addressed to make antibiotic discovery sustainable in the future.
抗生素是当前医学实践的重要组成部分，但由于抗菌药物耐药性感染的不断出现，其疗效正在逐渐减弱。与此同时，抗生素的发现速度已经放缓，我们未来治疗感染的能力受到了威胁。克里斯托弗·T·沃尔什（Christopher T. Walsh）对科学的众多贡献之一是，他很早就意识到了这一威胁，以及生物合成——基因和机制——可能为解决问题提供帮助。在这里，我们重温了沃尔什及其同事在 2006 年发表的一篇综述，该综述强调了抗生素天然产物发现的一个主要挑战：识别新的天然存在的抗生素的几率令人望而却步。该综述描述了减轻几率挑战的策略。这些策略在那之后的几年里被天然产物发现界广泛应用，并取得了一些有前景的发现。尽管取得了这些进展，但新型抗生素天然产物的稀缺性仍然是发现的障碍。我们将发现天然产物抗生素的挑战与识别新素数的过程进行了比较，素数也很难找到，尽管它是现代生活中不可或缺但却被低估的一个元素。我们提出，在发现管道早期纳入针对功能化合物的筛选是发现天然产物抗生素的关键，我们将回顾一些能够实现这一目标的最新进展，并讨论一些需要解决的剩余挑战，以使未来的抗生素发现能够可持续发展。
