These authors contributed equally to this work.
M.G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, David Braley Centre for Antibiotic Discovery, McMaster University, Hamilton, Ontario, L8S 4K1, Canada.
EcoSal Plus. 2021 Mar;9(2). doi: 10.1128/ecosalplus.ESP-0027-2020.
As the spread of antibiotic resistance threatens our ability to treat infections, avoiding the return of a preantibiotic era requires the discovery of new drugs. While therapeutic use of antibiotics followed by the inevitable selection of resistance is a modern phenomenon, these molecules and the genetic determinants of resistance were in use by environmental microbes long before humans discovered them. In this review, we discuss evidence that antibiotics and resistance were present in the environment before anthropogenic use, describing techniques including direct sampling of ancient DNA and phylogenetic analyses that are used to reconstruct the past. We also pay special attention to the ecological and evolutionary forces that have shaped the natural history of antibiotic biosynthesis, including a discussion of competitive versus signaling roles for antibiotics, proto-resistance, and substrate promiscuity of biosynthetic and resistance enzymes. Finally, by applying an evolutionary lens, we describe concepts governing the origins and evolution of biosynthetic gene clusters and cluster-associated resistance determinants. These insights into microbes' use of antibiotics in nature, a game they have been playing for millennia, can provide inspiration for discovery technologies and management strategies to combat the growing resistance crisis.
随着抗生素耐药性的传播威胁到我们治疗感染的能力，避免回到抗生素前时代需要发现新的药物。虽然抗生素的治疗用途，随后不可避免地会选择耐药性，这是现代的现象，但这些分子和耐药性的遗传决定因素在人类发现它们之前很久就已经被环境微生物使用了。在这篇综述中，我们讨论了抗生素和耐药性在人类使用之前就存在于环境中的证据，描述了包括直接采样古代 DNA 和系统发育分析在内的技术，这些技术用于重建过去。我们还特别关注塑造抗生素生物合成自然历史的生态和进化力量，包括抗生素竞争与信号作用、原耐药性以及生物合成和耐药酶的底物混杂性的讨论。最后，通过应用进化的视角，我们描述了控制生物合成基因簇和簇相关耐药决定因素起源和进化的概念。这些关于微生物在自然界中使用抗生素的见解——它们已经玩了几千年的游戏——可以为发现技术和管理策略提供灵感，以应对日益严重的耐药性危机。
