6032-95-7Relevant articles and documents
Investigation of (S)-(-)-acidomycin: A selective antimycobacterial natural product that inhibits biotin synthase
Bockman, Matthew R.,Engelhart, Curtis A.,Cramer, Julia D.,Howe, Michael D.,Mishra, Neeraj K.,Zimmerman, Matthew,Larson, Peter,Alvarez-Cabrera, Nadine,Park, Sae Woong,Boshoff, Helena I. M.,Bean, James M.,Young, Victor G.,Ferguson, David M.,Dartois, Veronique,Jarrett, Joseph T.,Schnappinger, Dirk,Aldrich, Courtney C.
, p. 598 - 617 (2019/02/14)
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 biotin biosynthetic pathway intermediates and subsequent biochemical studies confirmed acidomycin inhibits biotin synthesis 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 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.
