Sequence-structure-function characterization of the emerging tetracycline destructase family of antibiotic resistance enzymes

Blake, Kevin S.; Kumar, Hirdesh; Loganathan, Anisha; Williford, Emily E.; Diorio-Toth, Luke; Xue, Yao-Peng; Tang, Wai Kwan; Campbell, Tayte P.; Chong, David D.; Angtuaco, Steven; Wencewicz, Timothy A.; Tolia, Niraj H.; Dantas, Gautam

doi:10.1038/s42003-024-06023-w

Title: Sequence-structure-function characterization of the emerging tetracycline destructase family of antibiotic resistance enzymes

Journal Article · 16 March 2024 · Communications Biology

DOI: https://doi.org/10.1038/s42003-024-06023-w · OSTI ID:2469984

^[1]; Kumar, Hirdesh ^[2]; Loganathan, Anisha ^[1]; Williford, Emily E. ^[3];

^[1]; Xue, Yao-Peng ^[1];

^[2];

^[1];

^[1]; Angtuaco, Steven ^[1];

^[3];

^[2];

^[1]

Washington Univ., St. Louis, MO (United States). School of Medicine
National Institutes of Health (NIH), Bethesda, MD (United States)
Washington Univ., St. Louis, MO (United States)

Tetracycline destructases (TDases) are flavin monooxygenases which can confer resistance to all generations of tetracycline antibiotics. The recent increase in the number and diversity of reported TDase sequences enables a deep investigation of the TDase sequence-structure-function landscape. Here, we evaluate the sequence determinants of TDase function through two complementary approaches: (1) constructing profile hidden Markov models to predict new TDases, and (2) using multiple sequence alignments to identify conserved positions important to protein function. Using the HMM-based approach we screened 50 high-scoring candidate sequences in Escherichia coli, leading to the discovery of 13 new TDases. The X-ray crystal structures of two new enzymes from Legionella species were determined, and the ability of anhydrotetracycline to inhibit their tetracycline-inactivating activity was confirmed. Using the MSA-based approach we identified 31 amino acid positions 100% conserved across all known TDase sequences. The roles of these positions were analyzed by alanine-scanning mutagenesis in two TDases, to study the impact on cell and in vitro activity, structure, and stability. These results expand the diversity of TDase sequences and provide valuable insights into the roles of important residues in TDases, and flavin monooxygenases more broadly.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF); National Institutes of Health (NIH); National Science Foundation (NSF)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 2469984

Journal Information:: Communications Biology, Journal Name: Communications Biology Journal Issue: 1 Vol. 7; ISSN 2399-3642

Publisher:: Springer NatureCopyright Statement

Country of Publication:: United States

Language:: English

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60 APPLIED LIFE SCIENCES
Life Sciences & Biomedicine - Other Topics
Science & Technology - Other Topics

Title: Sequence-structure-function characterization of the emerging tetracycline destructase family of antibiotic resistance enzymes

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