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Antibiotic combinations reduce Staphylococcus aureus clearance

Author

Listed:
  • Viktória Lázár

    (Technion–Israel Institute of Technology
    HCEMM-BRC Pharmacodinamic Drug Interaction Research Group
    Institute of Biochemistry, Biological Research Centre)

  • Olga Snitser

    (Technion–Israel Institute of Technology)

  • Daniel Barkan

    (The Hebrew University of Jerusalem)

  • Roy Kishony

    (Technion–Israel Institute of Technology
    Technion–Israel Institute of Technology
    Technion–Israel Institute of Technology)

Abstract

The spread of antibiotic resistance is attracting increased attention to combination-based treatments. Although drug combinations have been studied extensively for their effects on bacterial growth1–11, much less is known about their effects on bacterial long-term clearance, especially at cidal, clinically relevant concentrations12–14. Here, using en masse microplating and automated image analysis, we systematically quantify Staphylococcus aureus survival during prolonged exposure to pairwise and higher-order cidal drug combinations. By quantifying growth inhibition, early killing and longer-term population clearance by all pairs of 14 antibiotics, we find that clearance interactions are qualitatively different, often showing reciprocal suppression whereby the efficacy of the drug mixture is weaker than any of the individual drugs alone. Furthermore, in contrast to growth inhibition6–10 and early killing, clearance efficacy decreases rather than increases as more drugs are added. However, specific drugs targeting non-growing persisters15–17 circumvent these suppressive effects. Competition experiments show that reciprocal suppressive drug combinations select against resistance to any of the individual drugs, even counteracting methicillin-resistant Staphylococcus aureus both in vitro and in a Galleria mellonella larva model. As a consequence, adding a β-lactamase inhibitor that is commonly used to potentiate treatment against β-lactam-resistant strains can reduce rather than increase treatment efficacy. Together, these results underscore the importance of systematic mapping the long-term clearance efficacy of drug combinations for designing more-effective, resistance-proof multidrug regimes.

Suggested Citation

  • Viktória Lázár & Olga Snitser & Daniel Barkan & Roy Kishony, 2022. "Antibiotic combinations reduce Staphylococcus aureus clearance," Nature, Nature, vol. 610(7932), pages 540-546, October.
  • Handle: RePEc:nat:nature:v:610:y:2022:i:7932:d:10.1038_s41586-022-05260-5
    DOI: 10.1038/s41586-022-05260-5
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    Cited by:

    1. Chih-Wei Chen & Nadja Leimer & Egor A. Syroegin & Clémence Dunand & Zackery P. Bulman & Kim Lewis & Yury S. Polikanov & Maxim S. Svetlov, 2023. "Structural insights into the mechanism of overcoming Erm-mediated resistance by macrolides acting together with hygromycin-A," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    2. Sean Cavany & Stella Nanyonga & Cathrin Hauk & Cherry Lim & Joel Tarning & Benn Sartorius & Christiane Dolecek & Céline Caillet & Paul N. Newton & Ben S. Cooper, 2023. "The uncertain role of substandard and falsified medicines in the emergence and spread of antimicrobial resistance," Nature Communications, Nature, vol. 14(1), pages 1-9, December.

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