Blake Kevin S, Xue Yao-Peng, Gillespie Vincent J, Fishbein Skye R S, Tolia Niraj H, Wencewicz Timothy A, Dantas Gautam
The Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO, USA.
Department of Pathology and Immunology, Division of Laboratory and Genomic Medicine, Washington University School of Medicine, St. Louis, MO, USA.
Nat Commun. 2025 Feb 7;16(1):1452. doi: 10.1038/s41467-025-56425-5.
The history of clinical resistance to tetracycline antibiotics is characterized by cycles whereby the deployment of a new generation of drug molecules is quickly followed by the discovery of a new mechanism of resistance. This suggests mechanism-specific selection by each tetracycline generation; however, the evolutionary dynamics of this remain unclear. Here, we evaluate 24 recombinant Escherichia coli strains expressing tetracycline resistance genes from each mechanism (efflux pumps, ribosomal protection proteins, and enzymatic inactivation) in the context of each tetracycline generation. We employ a high-throughput barcode sequencing protocol that can discriminate between strains in mixed culture and quantify their relative abundances. We find that each mechanism is preferentially selected for by specific antibiotic generations, leading to their expansion. Remarkably, the minimum inhibitory concentration associated with individual genes is secondary to resistance mechanism for inter-mechanism relative fitness, but it does explain intra-mechanism relative fitness. These patterns match the history of clinical deployment of tetracycline drugs and resistance discovery in pathogens.
四环素类抗生素临床耐药性的历史呈现出周期性特点，即新一代药物分子投入使用后很快就会发现新的耐药机制。这表明每一代四环素都存在针对特定机制的选择；然而，其进化动态仍不清楚。在这里，我们评估了24株表达来自每种机制（外排泵、核糖体保护蛋白和酶失活）的四环素抗性基因的重组大肠杆菌菌株，这些菌株处于每一代四环素的环境中。我们采用了一种高通量条形码测序方案，该方案可以区分混合培养中的菌株并量化它们的相对丰度。我们发现每种机制都被特定的抗生素代优先选择，从而导致它们的扩增。值得注意的是，与单个基因相关的最低抑菌浓度对于机制间的相对适应性而言仅次于耐药机制，但它确实解释了机制内的相对适应性。这些模式与四环素类药物的临床应用历史以及病原体中耐药性的发现相匹配。
