Publication date: Jan 17, 2019
The synthesis, absolute stereochemical configuration, complete biological characterization, mechanism of action and resistance, and pharmacokinetic properties of (S)-(-)-acidomycin is described. Acidomycin possesses promising antitubercular activity against a series of contemporary drug susceptible and drug-resistant M. tuberculosis strains (MICs = 0.096-6.2 uM), but is inactive against non-tuberculosis mycobacteria, 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 uM through the competitive inhibition of biotin synthase (BioB) and also stimulates unproductive cleavage of S-adenosylmethionine (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.
Bockman, Engelhart, C.A., Cramer, J.D., Howe, M., Mishra, N., Zimmerman, M., Larson, P., Alvarez-Cabrera, N., Park, S.W., Boshoff, H.I.M., Bean, J.M., , Young, Ferguson, D.M., , Dartois, Jarrett, J.T., Schnappinger, D., and Aldrich, C.C. Investigation of (S)-(-)-acidomycin: A selective antimycobacterial natural product that inhibits biotin synthase. 04168. 2019 ACS Infect Dis.
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