Investigation of ( S)-(-)-Acidomycin: A Selective Antimycobacterial Natural Product That Inhibits Biotin Synthase.

Journal:
ACS infectious diseases, Volume: 5, Issue: 4
Published:
April 12, 2019
PMID:
30652474
Authors:
Matthew R Bockman MR, Curtis A Engelhart CA, Julia D Cramer JD, Michael D Howe MD, Neeraj K Mishra NK, Matthew Zimmerman M, Peter Larson P, Nadine Alvarez-Cabrera N, Sae Woong Park SW, Helena I M Boshoff HIM, James M Bean JM, Victor G Young VG, David M Ferguson DM, Veronique Dartois V, Joseph T Jarrett JT, Dirk Schnappinger D, Courtney C Aldrich CC
Abstract:

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 K 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.