7U22

Mycobacterium tuberculosis RNA polymerase sigma A holoenzyme open promoter complex containing UMN-7

Summary for 7U22

• Entry DOI: 10.2210/pdb7u22/pdb
• Descriptor: DNA-directed RNA polymerase subunit alpha, MAGNESIUM ION, DNA-directed RNA polymerase subunit beta, ... (10 entities in total)
• Functional Keywords: transcription, inhibitor, rifabutin, transcription initiation, tuberculosis, mtb, mycobacterium tuberculosis, mycobacterium smegmatis, antibiotic
• Biological source: Mycobacterium tuberculosis; More
• Total number of polymer chains: 8
• Total formula weight: 435378.85

Authors

Molodtsov, V.,Ebright, R.H. (deposition date: 2022-02-22, release date: 2022-10-19, Last modification date: 2023-10-18)

Primary citation

Lan, T.,Ganapathy, U.S.,Sharma, S.,Ahn, Y.M.,Zimmerman, M.,Molodtsov, V.,Hegde, P.,Gengenbacher, M.,Ebright, R.H.,Dartois, V.,Freundlich, J.S.,Dick, T.,Aldrich, C.C.
Redesign of Rifamycin Antibiotics to Overcome ADP-Ribosylation-Mediated Resistance.
Angew.Chem.Int.Ed.Engl., 61:e202211498-e202211498, 2022

PubMed 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.

PubMed: 36222275
DOI: 10.1002/anie.202211498

Experimental method

X-RAY DIFFRACTION (3.87 Å)