Redesign of Rifamycin Antibiotics to Overcome ADP-Ribosylation-Mediated Resistance

Tian Lan, Uday S. Ganapathy, Sachin Sharma, Yong Mo Ahn, Matthew Zimmerman, Vadim Molodtsov, Pooja Hegde, Martin Gengenbacher, Richard H. Ebright, Véronique Dartois, Joel S. Freundlich, Thomas Dick, Courtney C. Aldrich

Research output: Contribution to journalArticlepeer-review

Abstract

Rifamycin antibiotics are a valuable class of antimicrobials for treating infections by mycobacteria and other persistent bacteria owing to their potent bactericidal activity against replicating and non-replicating pathogens. However, the clinical utility of rifamycins against Mycobacterium abscessus is seriously compromised by a novel resistance mechanism, namely, rifamycin inactivation by ADP-ribosylation. Using a structure-based approach, we rationally redesign rifamycins through strategic modification of the ansa-chain to block ADP-ribosylation while preserving on-target activity. Validated by a combination of biochemical, structural, and microbiological studies, the most potent analogs overcome ADP-ribosylation, restored their intrinsic low nanomolar activity and demonstrated significant in vivo antibacterial efficacy. Further optimization by tuning drug disposition properties afforded a preclinical candidate with remarkable potency and an outstanding pharmacokinetic profile.

Original languageEnglish (US)
Article numbere202211498
JournalAngewandte Chemie - International Edition
Volume61
Issue number45
DOIs
StatePublished - Nov 7 2022

Bibliographical note

Funding Information:
The NMR analysis in this research was supported by Grant 1S10OD021536 from National Institute of General Medical Sciences. The ESI‐MS measurements were performed at Mass Spectrometry Laboratory of Department of Chemistry at the University of Minnesota. We thank the in vivo and analytical chemistry teams of the Center of Discovery and Innovation for their excellent technical assistance. We are grateful to Wei Chang Huang (Taichung Veterans General Hospital, Taichung, Taiwan) for providing Bamboo and to Sung Jae Shin (Department of Microbiology, Yonsei University College of Medicine, Seoul, South Korea) and Won‐Jung Koh (Division of Pulmonary and Critical Care Medicine, Samsung Medical Center, Seoul, South Korea) for providing K21. Research reported in this work was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Numbers R01AI132374 (to T.D.), U19AI142731 (to T.D., J.F.S., R.H.E., and V.D.) and S10 OD023524 (to V.D.). We thank the Stanford Synchrotron Radiation Lightsource for beamline access and support with X‐ray data collection. The structural biology work also was supported by National Institutes of Health grant GM041376 to R.H.E. M. abscessus M. abscessus

Funding Information:
The NMR analysis in this research was supported by Grant 1S10OD021536 from National Institute of General Medical Sciences. The ESI-MS measurements were performed at Mass Spectrometry Laboratory of Department of Chemistry at the University of Minnesota. We thank the in vivo and analytical chemistry teams of the Center of Discovery and Innovation for their excellent technical assistance. We are grateful to Wei Chang Huang (Taichung Veterans General Hospital, Taichung, Taiwan) for providing M. abscessus Bamboo and to Sung Jae Shin (Department of Microbiology, Yonsei University College of Medicine, Seoul, South Korea) and Won-Jung Koh (Division of Pulmonary and Critical Care Medicine, Samsung Medical Center, Seoul, South Korea) for providing M. abscessus K21. Research reported in this work was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Numbers R01AI132374 (to T.D.), U19AI142731 (to T.D., J.F.S., R.H.E., and V.D.) and S10 OD023524 (to V.D.). We thank the Stanford Synchrotron Radiation Lightsource for beamline access and support with X-ray data collection. The structural biology work also was supported by National Institutes of Health grant GM041376 to R.H.E.

Publisher Copyright:
© 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.

Keywords

  • Antibiotic Resistance
  • Antibiotics
  • Drug Design
  • Mycobacterium Abscessus
  • Rifamycin
  • Microbial Sensitivity Tests
  • Mycobacterium
  • Rifamycins/pharmacology
  • ADP-Ribosylation
  • Anti-Bacterial Agents/pharmacology

PubMed: MeSH publication types

  • Journal Article

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