Data_Sheet_2_The fitness cost of horizontally transferred and mutational antimicrobial resistance in Escherichia coli.XLSX

Antimicrobial resistance (AMR) in bacteria implies a tradeoff between the benefit of resistance under antimicrobial selection pressure and the incurred fitness cost in the absence of antimicrobials. The fitness cost of a resistance determinant is expected to depend on its genetic support, such as a chromosomal mutation or a plasmid acquisition, and on its impact on cell metabolism, such as an alteration in an essential metabolic pathway or the production of a new enzyme. To provide a global picture of the factors that influence AMR fitness cost, we conducted a systematic review and meta-analysis focused on a single species, Escherichia coli. By combining results from 46 high-quality studies in a multilevel meta-analysis framework, we find that the fitness cost of AMR is smaller when provided by horizontally transferable genes such as those encoding beta-lactamases, compared to mutations in core genes such as those involved in fluoroquinolone and rifampicin resistance. We observe that the accumulation of acquired AMR genes imposes a much smaller burden on the host cell than the accumulation of AMR mutations, and we provide quantitative estimates of the additional cost of a new gene or mutation. These findings highlight that gene acquisition is more efficient than the accumulation of mutations to evolve multidrug resistance, which can contribute to the observed dominance of horizontally transferred genes in the current AMR epidemic.

细菌的抗菌药物耐药性（Antimicrobial resistance, AMR）意味着在抗菌药物选择压力下耐药性带来的生存优势，与无抗菌药物环境下所需付出的适合度代价之间存在权衡。某一耐药决定因子的适合度代价，取决于其遗传背景——如染色体突变或质粒获取——以及其对细胞代谢的影响——如核心代谢通路的改变或新酶的产生。为全面解析影响抗菌药物耐药性适合度代价的各类因素，本研究针对单一物种大肠杆菌（Escherichia coli）开展了系统综述与元分析。通过在多水平元分析框架中整合46项高质量研究的结果，我们发现：相较于氟喹诺酮类、利福平耐药相关核心基因的突变，由可水平转移基因（如编码β-内酰胺酶的基因）所赋予的抗菌药物耐药性适合度代价更低。我们还观察到，获得性抗菌耐药基因的累积对宿主细胞造成的负担，远低于抗菌耐药突变的累积，并给出了新增单个基因或突变所带来额外代价的定量估算值。上述研究结果表明，相较于突变累积，基因获取在演化多药耐药的过程中更为高效，这或许可以解释当前抗菌药物耐药性流行中水平转移基因占主导地位的现象。