期刊
ACS INFECTIOUS DISEASES
卷 5, 期 4, 页码 598-617出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsinfecdis.8b00345
关键词
Mycobacterium tuberculosis; tuberculosis; biotin biosynthesis; biotin synthase; antimetabolite; acidomycin; accumulation
资金
- National Institutes of Health [AI091790]
- Intramural Research Program of NIAID [AI000693-25]
- NIH Shared Instrumentation Grant [S10-OD017982]
- NSF/MRI [1229400]
- University of Minnesota
- NCI Cancer Center Support Grant (CCSG) [P30 CA08748]
- Cycle for Survival
- Marie-Josee and Henry R. Kravis Center for Molecular Oncology
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [ZIAAI000693] Funding Source: NIH RePORTER
The synthesis, absolute stereochemical configuration, complete biological characterization, mechanism of action and resistance, and pharmacokinetic properties of (S)-(-)-acidomycin are described. Acidomycin possesses promising antitubercular activity against a series of contemporary drug susceptible and drug-resistant M. tuberculosis strains (minimum inhibitory concentrations (MICs) = 0.096-6.2 mu M) but is inactive against nontuberculosis mycobacteria and Gram-positive and Gram-negative pathogens (MICs > 1000 mu M). Complementation studies with biotin biosynthetic pathway intermediates and subsequent biochemical studies confirmed acidomycin inhibits biotin synthesis with a K-i of approximately 1 mu M through the competitive inhibition of biotin synthase (BioB) and also stimulates unproductive cleavage of S-adenosyl-L-methionine (SAM) to generate the toxic metabolite 5'-deoxyadenosine. Cell studies demonstrate acidomycin selectively accumulates in M. tuberculosis providing a mechanistic basis for the observed antibacterial activity. The development of spontaneous resistance by M. tuberculosis to acidomycin was difficult, and only low-level resistance to acidomycin was observed by overexpression of BioB. Collectively, the results provide a foundation to advance acidomycin and highlight BioB as a promising target.
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