C10-Benzoate Esters of Anhydrotetracycline Inhibit Tetracycline Destructases and Recover Tetracycline Antibacterial Activity
[2];
[5];
[1]
- Washington University in Saint Louis, MO (United States)
- National Institutes of Health, Bethesda, MD (United States)
- Department of Chemistry; Washington University in St. Louis
- Washington University School of Medicine, St. Louis, MO (United States)
- Washington University School of Medicine, St. Louis, MO (United States); Washington University in St. Louis, MO (United States)
Tetracyclines (TCs) are an important class of antibiotics threatened by enzymatic inactivation. These tetracycline-inactivating enzymes, also known as tetracycline destructases (TDases), are a subfamily of class A flavin monooxygenases (FMOs) that catalyze hydroxyl group transfer and oxygen insertion (Baeyer–Villiger type) reactions on TC substrate scaffolds. Semisynthetic modification of TCs (e.g., tigecycline, omadacycline, eravacycline, and sarecycline) has proven effective in evading certain resistance mechanisms, such as ribosomal protection and efflux, but does not protect against TDase-mediated resistance. Here, we report the design, synthesis, and evaluation of a new series of 22 semisynthetic TDase inhibitors that explore D-ring substitution of anhydrotetracycline (aTC) including 14 C10-benzoate ester and eight C9-benzamides. Overall, the C10-benzoate esters displayed enhanced bioactivity and water solubility compared to the corresponding C9-benzamides featuring the same heterocyclic aryl side chains. The C10-benzoate ester derivatives of aTC were prepared in a high-yield one-step synthesis without the need for protecting groups. The C10-esters are water-soluble, stable toward hydrolysis, and display dose-dependent rescue of tetracycline antibiotic activity in E. coli expressing two types of tetracycline destructases, represented by TetX7 (Type 1) and Tet50 (Type 2). The best inhibitors recovered tetracycline antibiotic activity at concentrations as low as 2 μM, producing synergistic scores <0.5 in the fractional inhibitory concentration index (FICI) against TDase-expressing strains of E. coli and clinical P. aeruginosa. The C10-benzoate ester derivatives of aTC reported here are promising new leads for the development of tetracycline drug combination therapies to overcome TDase-mediated antibiotic resistance.
- Research Organization:
- Washington University in Saint Louis, MO (United States)
- Sponsoring Organization:
- National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH); National Institutes of Health, National Institute of General Medical Sciences; South East Regional Collaborative Access Team (SER-CAT); USDOE Office of Science (SC), Basic Energy Sciences (BES); USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF)
- Grant/Contract Number:
- AC02-05CH11231
- OSTI ID:
- 2531032
- Journal Information:
- ACS Infectious Diseases, Journal Name: ACS Infectious Diseases Journal Issue: 3 Vol. 11; ISSN 2373-8227
- Publisher:
- American Chemical Society (ACS)Copyright Statement
- Country of Publication:
- United States
- Language:
- English
Similar Records
Sarecycline interferes with tRNA accommodation and tethers mRNA to the 70S ribosome
EXPERIMENTAL DATA ON INCREASING RESISTANCE OF RATS TO RADIATION SICKNESS IN PREVIOUS INTRODUCTION OF TETRACYCLINES