Jiangsu Provincial Key Lab for the Chemistry and Utilization of Agro-Forest Biomass, Jiangsu Co-Innovation Center of Efficient Processing and Utilization of Forest Resources, Jiangsu Key Lab of Biomass-Based Green Fuels and Chemicals, Nanjing Forestry University, Nanjing 210037, Jiangsu China.
Department of Pharmaceutical Chemistry and Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California 94158, United States.
Acc Chem Res. 2021 Apr 20;54(8):1891-1908. doi: 10.1021/acs.accounts.0c00894. Epub 2021 Apr 1.
Continued, rapid development of antimicrobial resistance has become worldwide health crisis and a burden on the global economy. Decisive and comprehensive action is required to slow down the spread of antibiotic resistance, including increased investment in antibiotic discovery, sustainable policies that provide returns on investment for newly launched antibiotics, and public education to reduce the overusage of antibiotics, especially in livestock and agriculture. Without significant changes in the current antibiotic pipeline, we are in danger of entering a post-antibiotic era.In this Account, we summarize our recent efforts to develop next-generation streptogramin and lankacidin antibiotics that overcome bacterial resistance by means of modular chemical synthesis. First, we describe our highly modular, scalable route to four natural group A streptogramins antibiotics in 6-8 steps from seven simple chemical building blocks. We next describe the application of this route to the synthesis of a novel library of streptogramin antibiotics informed by in vitro and in vivo biological evaluation and high-resolution cryo-electron microscopy. One lead compound showed excellent inhibitory activity in vitro and in vivo against a longstanding streptogramin-resistance mechanism, virginiamycin acetyltransferase. Our results demonstrate that the combination of rational design and modular chemical synthesis can revitalize classes of antibiotics that are limited by naturally arising resistance mechanisms.Second, we recount our modular approaches toward lankacidin antibiotics. Lankacidins are a group of polyketide natural products with activity against several strains of Gram-positive bacteria but have not been deployed as therapeutics due to their chemical instability. We describe a route to several diastereomers of 2,18--lankacidinol B in a linear sequence of ≤8 steps from simple building blocks, resulting in a revision of the C4 stereochemistry. We next detail our modular synthesis of several diastereoisomers of -lankacidinol that resulted in the structural reassignment of this natural product. These structural revisions raise interesting questions about the biosynthetic origin of lankacidins, all of which possessed uniform stereochemistry prior to these findings. Finally, we summarize the ability of several - and -lankacidins to inhibit the growth of bacteria and to inhibit translation in vitro, providing important insights into structure-function relationships for the class.
抗菌药物耐药性的持续快速发展已成为全球健康危机，给全球经济带来沉重负担。为了减缓抗生素耐药性的传播，需要采取果断和全面的行动，包括增加抗生素研发投入、制定可持续的政策，为新推出的抗生素投资提供回报，以及开展公众教育，减少抗生素的过度使用，尤其是在畜牧业和农业领域。如果当前的抗生素研发管线没有重大变化，我们将面临进入后抗生素时代的危险。在本专题介绍中，我们总结了最近通过模块化化学合成开发新一代链阳性菌素和林可酰胺类抗生素的努力，这些抗生素通过化学合成克服了细菌耐药性。首先，我们描述了一种高度模块化、可扩展的方法，从七个简单的化学起始原料出发，经过 6-8 步反应可以合成四种天然 A 组链阳性菌素抗生素。接下来，我们描述了该路线在合成新型链阳性菌素抗生素文库中的应用，该文库的设计基于体外和体内生物学评价以及高分辨率冷冻电镜的结果。一个先导化合物对一种长期存在的链阳性菌素耐药机制（维吉尼亚霉素乙酰转移酶）表现出优异的体外和体内抑制活性。我们的结果表明，理性设计和模块化化学合成的结合可以使受到天然耐药机制限制的抗生素类别重新焕发生机。其次，我们回顾了模块化方法在林可酰胺类抗生素中的应用。林可酰胺类是一组具有抗几种革兰氏阳性菌活性的聚酮类天然产物，但由于其化学不稳定性，尚未作为治疗药物使用。我们描述了一种从简单起始原料出发，经过≤8 步线性反应合成 2,18--林可酸醇 B 的几种非对映异构体的方法，该方法导致 C4 立体化学的修订。接下来，我们详细介绍了我们对几种林可酸醇非对映异构体的模块化合成，该合成导致了该天然产物的结构重新分配。这些结构修订提出了关于林可酰胺类生物合成起源的有趣问题，在这些发现之前，所有林可酰胺类化合物都具有一致的立体化学。最后，我们总结了几种 -和 -林可酰胺类抑制细菌生长和体外翻译的能力，为该类化合物提供了结构-功能关系的重要见解。
