Investigation of (S)-(-)-acidomycin: A selective antimycobacterial natural product that inhibits biotin synthase

Matthew R. Bockman, Curtis A. Engelhart, Julia D. Cramer, Michael D. Howe, Neeraj K Mishra, Matthew Zimmerman, Peter Larson, Nadine Alvarez-Cabrera, Sae Woong Park, Helena I.M. Boshoff, James M. Bean, Victor G Young, David M Ferguson, Veronique Dartois, Joseph T. Jarrett, Dirk Schnappinger, Courtney Aldrich

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)598-617
Number of pages20
JournalACS Infectious Diseases
Volume5
Issue number4
DOIs
StatePublished - Apr 12 2019

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Biological Products
Microbial Sensitivity Tests
Biotin
Tuberculosis
Multidrug-Resistant Tuberculosis
Poisons
Biosynthetic Pathways
Mycobacterium
mycobacidin
biotin synthetase
Methionine
Pharmacokinetics
Pharmaceutical Preparations

Keywords

  • Mycobacterium tuberculosis
  • accumulation
  • acidomycin
  • antimetabolite
  • biotin biosynthesis
  • biotin synthase
  • tuberculosis

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

Cite this

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.

In: ACS Infectious Diseases, Vol. 5, No. 4, 12.04.2019, p. 598-617.

Research output: Contribution to journalArticle

Bockman, MR, Engelhart, CA, Cramer, JD, Howe, MD, Mishra, NK, Zimmerman, M, Larson, P, Alvarez-Cabrera, N, Park, SW, Boshoff, HIM, Bean, JM, Young, VG, Ferguson, DM, Dartois, V, Jarrett, JT, Schnappinger, D & Aldrich, C 2019, 'Investigation of (S)-(-)-acidomycin: A selective antimycobacterial natural product that inhibits biotin synthase', ACS Infectious Diseases, vol. 5, no. 4, pp. 598-617. https://doi.org/10.1021/acsinfecdis.8b00345
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. / Investigation of (S)-(-)-acidomycin : A selective antimycobacterial natural product that inhibits biotin synthase. In: ACS Infectious Diseases. 2019 ; Vol. 5, No. 4. pp. 598-617.
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