美国麻省理工学院James J. Collins研究团队发现，核心代谢基因的临床相关突变赋予抗生素耐药性。这一研究成果于2021年2月19日发表在国际学术期刊《科学》上。

研究人员对代谢状态日益提高，并使其适应代表性抗生素的大肠杆菌进行了测序和分析。这揭示了各种与抗生素抗性有关的被低估的非经典基因，例如与核心碳和能量代谢有关的。这些代谢改变导致较低的基础呼吸，从而阻止了抗生素介导的三羧酸循环活性的诱导，进而避免了代谢毒性并使药物致死率最小化。在超过3500种临床大肠杆菌病原体的基因组中，研究人员鉴定出了几种新陈代谢特异的显著突变，从而表明了临床相关性。

据了解，尽管新陈代谢在抗生素致死率中起着积极作用，但抗生素抗性通常与药物靶标修饰、酶促失活和/或转运有关，而不是与代谢过程有关。大肠杆菌的进化实验取决于生长依赖性的选择，这可能会提供有限的抗生素耐药观点。

附：英文原文

Title: Clinically relevant mutations in core metabolic genes confer antibiotic resistance

Author: Allison J. Lopatkin, Sarah C. Bening, Abigail L. Manson, Jonathan M. Stokes, Michael A. Kohanski, Ahmed H. Badran, Ashlee M. Earl, Nicole J. Cheney, Jason H. Yang, James J. Collins

Issue&Volume: 2021/02/19

Abstract: Although metabolism plays an active role in antibiotic lethality, antibiotic resistance is generally associated with drug target modification, enzymatic inactivation, and/or transport rather than metabolic processes. Evolution experiments of Escherichia coli rely on growth-dependent selection, which may provide a limited view of the antibiotic resistance landscape. We sequenced and analyzed E. coli adapted to representative antibiotics at increasingly heightened metabolic states. This revealed various underappreciated noncanonical genes, such as those related to central carbon and energy metabolism, which are implicated in antibiotic resistance. These metabolic alterations lead to lower basal respiration, which prevents antibiotic-mediated induction of tricarboxylic acid cycle activity, thus avoiding metabolic toxicity and minimizing drug lethality. Several of the identified metabolism-specific mutations are overrepresented in the genomes of >3500 clinical E. coli pathogens, indicating clinical relevance.

DOI: 10.1126/science.aba0862

Source: https://science.sciencemag.org/content/371/6531/eaba0862