Semisynthetic analogues of anhydrotetracycline as inhibitors of tetracycline destructase enzymes

Jana L. Markley, Luting Fang, Andrew J. Gasparrini, Chanez T. Symister, Hirdesh Kumar, Niraj H. Tolia, Gautam Dantas, Timothy A. Wencewicz

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

The synthesis and biological evaluation of semisynthetic anhydrotetracycline analogues as small molecule inhibitors of tetracycline-inactivating enzymes are reported. Inhibitor potency was found to vary as a function of enzyme (major) and substrate-inhibitor pair (minor), and anhydrotetracycline analogue stability to enzymatic and nonenzymatic degradation in solution contributes to their ability to rescue tetracycline activity in whole cell Escherichia coli expressing tetracycline destructase enzymes. Taken collectively, these results provide the framework for the rational design of next-generation inhibitor libraries en route to a viable and proactive adjuvant approach to combat the enzymatic degradation of tetracycline antibiotics.

Original languageEnglish
Pages (from-to)618-633
Number of pages16
JournalACS Infectious Diseases
Volume5
Issue number4
DOIs
StatePublished - Apr 12 2019

Keywords

  • Tet(X)
  • anhydrotetracycline
  • antibiotic adjuvants
  • antibiotic resistance
  • enzymology
  • eravacycline
  • inactivating enzymes
  • omadacycline
  • tetracycline destructases
  • tetracyclines
  • tigecycline

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    Markley, J. L., Fang, L., Gasparrini, A. J., Symister, C. T., Kumar, H., Tolia, N. H., Dantas, G., & Wencewicz, T. A. (2019). Semisynthetic analogues of anhydrotetracycline as inhibitors of tetracycline destructase enzymes. ACS Infectious Diseases, 5(4), 618-633. https://doi.org/10.1021/acsinfecdis.8b00349