Investigation of (S)-(-)-acidomycin: A selective antimycobacterial natural product that inhibits biotin synthase Journal Article
| Authors: | Bockman, M. R.; Engelhart, C. A.; Cramer, J. D.; Howe, M. D.; Mishra, N. K.; Zimmerman, M.; Larson, P.; Alvarez-Cabrera, N.; Park, S. W.; Boshoff, H. I. M.; Bean, J. M.; Young, V. G. Jr; Ferguson, D. M.; Dartois, V.; Jarrett, J. T.; Schnappinger, D.; Aldrich, C. C. |
| Article Title: | Investigation of (S)-(-)-acidomycin: A selective antimycobacterial natural product that inhibits biotin synthase |
| 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 i 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. © 2019 American Chemical Society. |
| Keywords: | unclassified drug; area under the curve; nonhuman; ultraviolet radiation; animal cell; mouse; animal experiment; in vivo study; in vitro study; drug selectivity; drug synthesis; bacterial strain; biosynthesis; mycobacterium tuberculosis; drug research; drug accumulation; drug mechanism; escherichia coli; western blotting; mycobacterium bovis; nuclear magnetic resonance spectroscopy; single drug dose; gentamicin; high performance liquid chromatography; drug half life; staphylococcus aureus; natural product; crystallization; mycobacterium; microbiological examination; metabolite; thin layer chromatography; tuberculosis; antimetabolite; stereochemistry; bioavailability; proton nuclear magnetic resonance; acinetobacter baumannii; drug formulation; biotinylation; growth inhibition; mycobacterium smegmatis; x ray diffraction; colony forming unit; dna isolation; cytotoxicity assay; operon; pseudomonas aeruginosa; antibacterial activity; s adenosylmethionine; reversed phase liquid chromatography; mycobacterium abscessus; enantiomer; minimum inhibitory concentration; reversed phase high performance liquid chromatography; microbial activity; liquid chromatography-mass spectrometry; accumulation; tuberculostatic agent; enterococcus faecalis; deoxyadenosine derivative; priority journal; article; whole genome sequencing; far western blotting; volume of distribution; vero cell line; acidomycin; biotin biosynthesis; biotin synthase; 5' deoxyadenosine; 6 (4 oxothiazolidin 2 yl)hexanoic acid; methyl 6 (4 oxothiazolidin 2 yl)hexanoate; methyl 7 hydroxyheptanoate; methyl pimelate semialdehyde; accumulation assay; bacteriostatic activity; hep-g2 cell line; mycobacterium africanum; mycobacterium avium complex |
| Journal Title: | ACS Infectious Diseases |
| Volume: | 5 |
| Issue: | 4 |
| ISSN: | 2373-8227 |
| Publisher: | American Chemical Society |
| Date Published: | 2019-04-12 |
| Start Page: | 598 |
| End Page: | 617 |
| Language: | English |
| DOI: | 10.1021/acsinfecdis.8b00345 |
| PUBMED: | 30652474 |
| PROVIDER: | scopus |
| PMCID: | PMC6724193 |
| DOI/URL: | |
| Notes: | Source: Scopus |
