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The tetracycline resistome is shaped by selection for specific resistance mechanisms by each antibiotic generation

Author

Listed:
  • Kevin S. Blake

    (Washington University School of Medicine
    Washington University School of Medicine)

  • Yao-Peng Xue

    (Washington University School of Medicine)

  • Vincent J. Gillespie

    (Washington University School of Medicine)

  • Skye R. S. Fishbein

    (Washington University School of Medicine
    Washington University School of Medicine)

  • Niraj H. Tolia

    (National Institutes of Health)

  • Timothy A. Wencewicz

    (Washington University in St. Louis)

  • Gautam Dantas

    (Washington University School of Medicine
    Washington University School of Medicine
    Washington University School of Medicine
    Washington University in St. Louis)

Abstract

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.

Suggested Citation

  • Kevin S. Blake & Yao-Peng Xue & Vincent J. Gillespie & Skye R. S. Fishbein & Niraj H. Tolia & Timothy A. Wencewicz & Gautam Dantas, 2025. "The tetracycline resistome is shaped by selection for specific resistance mechanisms by each antibiotic generation," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56425-5
    DOI: 10.1038/s41467-025-56425-5
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    References listed on IDEAS

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    1. Eric D. Kelsic & Jeffrey Zhao & Kalin Vetsigian & Roy Kishony, 2015. "Counteraction of antibiotic production and degradation stabilizes microbial communities," Nature, Nature, vol. 521(7553), pages 516-519, May.
    2. Violette Da Cunha & Mark R. Davies & Pierre-Emmanuel Douarre & Isabelle Rosinski-Chupin & Immaculada Margarit & Sebastien Spinali & Tim Perkins & Pierre Lechat & Nicolas Dmytruk & Elisabeth Sauvage & , 2014. "Streptococcus agalactiae clones infecting humans were selected and fixed through the extensive use of tetracycline," Nature Communications, Nature, vol. 5(1), pages 1-12, December.
    3. Michelle F. Richter & Bryon S. Drown & Andrew P. Riley & Alfredo Garcia & Tomohiro Shirai & Riley L. Svec & Paul J. Hergenrother, 2017. "Predictive compound accumulation rules yield a broad-spectrum antibiotic," Nature, Nature, vol. 545(7654), pages 299-304, May.
    4. Wen Li & Gemma C. Atkinson & Nehal S. Thakor & Ülar Allas & Chuao-chao Lu & Kwok-Yan Chan & Tanel Tenson & Klaus Schulten & Kevin S. Wilson & Vasili Hauryliuk & Joachim Frank, 2013. "Mechanism of tetracycline resistance by ribosomal protection protein Tet(O)," Nature Communications, Nature, vol. 4(1), pages 1-8, June.
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