Structure of anhydrotetracycline-bound Tet(X6) reveals the mechanism for inhibition of type 1 tetracycline destructases

Autor: Hirdesh Kumar, Emily E. Williford, Kevin S. Blake, Brett Virgin-Downey, Gautam Dantas, Timothy A. Wencewicz, Niraj H. Tolia
Jazyk: angličtina
Rok vydání: 2023
Předmět:
Zdroj: Communications Biology, Vol 6, Iss 1, Pp 1-10 (2023)
Druh dokumentu: article
ISSN: 2399-3642
DOI: 10.1038/s42003-023-04792-4
Popis: Abstract Inactivation of tetracycline antibiotics by tetracycline destructases (TDases) remains a clinical and agricultural threat. TDases can be classified as type 1 Tet(X)-like TDases and type 2 soil-derived TDases. Type 1 TDases are widely identified in clinical pathogens. A combination therapy of tetracycline and a TDase inhibitor is much needed to rescue the clinical efficacy of tetracyclines. Anhydrotetracycline is a pan-TDase inhibitor that inhibits both type 1 and type 2 TDases. Here, we present structural, biochemical, and phenotypic evidence that anhydrotetracycline binds in a substrate-like orientation and competitively inhibits the type 1 TDase Tet(X6) to rescue tetracycline antibiotic activity as a sacrificial substrate. Anhydrotetracycline interacting residues of Tet(X6) are conserved within type 1 TDases, indicating a conserved binding mode and mechanism of inhibition. This mode of binding and inhibition is distinct from anhydrotetracycline’s inhibition of type 2 TDases. This study forms the framework for development of next-generation therapies to counteract enzymatic tetracycline resistance.
Databáze: Directory of Open Access Journals
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