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ACS Infect Dis. 2019 Mar 5. doi: 10.1021/acsinfecdis.8b00349. [Epub ahead of print]

Semisynthetic Analogues of Anhydrotetracycline as Inhibitors of Tetracycline Destructase Enzymes.

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The Edison Family Center for Genome Sciences & Systems Biology , Washington University School of Medicine , 4513 Clayton Ave. , Campus Box 8510, St. Louis , Missouri 63108 , United States.
Laboratory of Malaria Immunology and Vaccinology , National Institute of Allergy and Infectious Diseases , National Institutes of Health, 9000 Rockville Pike , BG 29B Rm 4NN08, Bethesda , Maryland 20814 , United States.
Department of Pathology and Immunology , Washington University School of Medicine , St. Louis , Missouri 63110 , United States.
Department of Molecular Microbiology , Washington University School of Medicine , 4515 McKinley Avenue, fifth Floor, Room 5314 , St. Louis , Missouri 63110 , United States.


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.


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

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