Investigation of (S)-(−)-Acidomycin: A Selective Antimycobacterial Natural Product That Inhibits Biotin Synthase
2019
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 μM) but is inactive against nontuberculosis mycobacteria and Gram-positive and Gram-negative pathogens (MICs > 1000 μM). Complementation studies with
biotinbiosynthetic pathway intermediates and subsequent biochemical studies confirmed acidomycin inhibits
biotinsynthesis with a Ki of approximately 1 μM 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 an...
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