TY - JOUR
T1 - Semisynthetic analogues of anhydrotetracycline as inhibitors of tetracycline destructase enzymes
AU - Markley, Jana L.
AU - Fang, Luting
AU - Gasparrini, Andrew J.
AU - Symister, Chanez T.
AU - Kumar, Hirdesh
AU - Tolia, Niraj H.
AU - Dantas, Gautam
AU - Wencewicz, Timothy A.
N1 - Funding Information:
The authors would like to thank Washington Univ. in St. Louis (WUSTL), Washington Univ. School of Medicine, and the National Institutes of Health for their support of this research and our programs. In particular, N.T. would like to thank the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, for the support of his program. We would also like to acknowledge J. Kao and M. Singh (WUSTL, Dept. of Chemistry) for their assistance with NMR experiments and B. Evans (Danforth Plant Science Center, St. Louis, MO) and his team for their assistance in acquiring high-resolution mass spectra for all synthesized compounds. In addition, J.L.M. would like to acknowledge the WM Keck Postdoctoral Program in Molecular Medicine for funding support of her postdoctoral fellowship.
Funding Information:
*E-mail: [email protected]. (T.A.W.) *E-mail: [email protected]. (G.D.) *E-mail: [email protected]. (N.H.T.) ORCID Jana L. Markley: 0000-0001-6855-7161 Andrew J. Gasparrini: 0000-0002-4551-4633 Hirdesh Kumar: 0000-0002-8488-3001 Niraj H. Tolia: 0000-0002-2689-1337 Gautam Dantas: 0000-0003-0455-8370 Timothy A. Wencewicz: 0000-0002-5839-6672 Author Contributions ∇These authors jointly supervised this work. The manuscript was written through the collaborative contributions of all authors. All authors have given approval to the final version of the manuscript. Funding This research is supported by the National Institute of Allergy and Infectious Diseases (NIAID-NIH R01-123394). N.T. is supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. J.L.M. is supported by the W. M. Keck Program in Molecular Medicine. Notes The authors declare no competing financial interest.
Publisher Copyright:
© 2019 American Chemical Society.
PY - 2019/4/12
Y1 - 2019/4/12
N2 - 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.
AB - 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.
KW - Tet(X)
KW - anhydrotetracycline
KW - antibiotic adjuvants
KW - antibiotic resistance
KW - enzymology
KW - eravacycline
KW - inactivating enzymes
KW - omadacycline
KW - tetracycline destructases
KW - tetracyclines
KW - tigecycline
UR - http://www.scopus.com/inward/record.url?scp=85062877659&partnerID=8YFLogxK
U2 - 10.1021/acsinfecdis.8b00349
DO - 10.1021/acsinfecdis.8b00349
M3 - Article
C2 - 30835428
AN - SCOPUS:85062877659
SN - 2373-8227
VL - 5
SP - 618
EP - 633
JO - ACS Infectious Diseases
JF - ACS Infectious Diseases
IS - 4
ER -