Summary information and primary citation
- PDB-id
-
7u22;
SNAP-derived features in text and
JSON formats
- Class
- antibiotic
- Method
- X-ray (3.87 Å)
- Summary
- Mycobacterium tuberculosis RNA polymerase sigma a
holoenzyme open promoter complex containing umn-7
- Reference
-
Lan T, Ganapathy US, Sharma S, Ahn YM, Zimmerman M,
Molodtsov V, Hegde P, Gengenbacher M, Ebright RH, Dartois
V, Freundlich JS, Dick T, Aldrich CC (2022): "Redesign
of Rifamycin Antibiotics to Overcome
ADP-Ribosylation-Mediated Resistance."
Angew.Chem.Int.Ed.Engl., 61,
e202211498. doi: 10.1002/anie.202211498.
- 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.
