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

doi:10.1021/acsinfecdis.8b00345

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 journal › Article › peer-review

20 Scopus citations

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 language	English (US)
Pages (from-to)	598-617
Number of pages	20
Journal	ACS Infectious Diseases
Volume	5
Issue number	4
DOIs	https://doi.org/10.1021/acsinfecdis.8b00345
State	Published - Apr 12 2019

Bibliographical note

Funding Information:
This work was supported by a grant (AI091790 to D.S.) from the National Institutes of Health and in part by the Intramural Research Program of NIAID (AI000693-25). Mass spectrometry was carried out in the Center for Mass Spectrometry and Proteomics, University of Minnesota. Isothermal titration calorimetry was carried out using an ITC-200 microcalorimeter, funded by the NIH Shared Instrumentation Grant S10-OD017982. The Bruker-AXS D8 Venture diffractometer was purchased through a grant from NSF/MRI (#1229400) and the University of Minnesota. We gratefully acknowledge Colin Manoil for supplying A. baumannii AB5075, Ryan Hunter for supplying S. aureus USA300 and P. aeruginosa PA14, and Gary Dunny for suppling E. faecalis V583. We acknowledge the use of the Integrated Genomics Operation Core at MSKCC, funded by the NCI Cancer Center Support Grant (CCSG, P30 CA08748), Cycle for Survival, and the Marie-Joseé and Henry R. Kravis Center for Molecular Oncology. The authors acknowledge the Minnesota Supercomputing Institute (MSI) at the University of Minnesota.

Funding Information:
This work was supported by a grant (AI091790 to D.S.) from the National Institutes of Health and in part by the Intramural Research Program of NIAID (AI000693-25). Mass spectrometry was carried out in the Center for Mass Spectrometry and Proteomics, University of Minnesota. Isothermal titration calorimetry was carried out using an ITC-200 microcalorimeter, funded by the NIH Shared Instrumentation Grant S10-OD017982. The Bruker-AXS D8 Venture diffractometer was purchased through a grant from NSF/MRI (#1229400) and the University of Minnesota. We gratefully acknowledge Colin Manoil for supplying A. baumannii AB5075, Ryan Hunter for supplying S. aureus USA300 and P. aeruginosa PA14, and Gary Dunny for suppling E. faecalis V583. We acknowledge the use of the Integrated Genomics Operation Core at MSKCC, funded by the NCI Cancer Center Support Grant (CCSG, P30 CA08748), Cycle for Survival, and the Marie-Josei? and Henry R. Kravis Center for Molecular Oncology. The authors acknowledge the Minnesota Supercomputing Institute (MSI) at the University of Minnesota.

Funding Information:
†Department of Medicinal Chemistry, University of Minnesota, 308 Harvard Street SE, Minneapolis, Minnesota 55455, United States ‡Department of Microbiology and Immunology, Weill Cornell Medical College, 1300 York Avenue, New York, New York 10021, United States §Department of Chemistry, University of Hawaii at Manoa, 2545 McCarthy Mall, Honolulu, Hawaii 96822, United States ∥Public Health Research Institute, Rutgers, The State University of New Jersey, 225 Warren Street, Newark, New Jersey 07103, United States ⊥Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, 5601 Fishers Lane, Bethesda, Maryland 20892, United States #Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, United States ○X-Ray Crystallographic Laboratory, LeClaire-Dow Chemical Instrumentation Facility, Department of Chemistry, University of Minnesota, 207 Pleasant Street SE, Minneapolis, Minnesota 55455, United States

Publisher Copyright:
© 2019 American Chemical Society.

Keywords

Mycobacterium tuberculosis
accumulation
acidomycin
antimetabolite
biotin biosynthesis
biotin synthase
tuberculosis

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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., Ferguson, D. M., Dartois, V., Jarrett, J. T., Schnappinger, D., & Aldrich, C. (2019). Investigation of (S)-(-)-acidomycin: A selective antimycobacterial natural product that inhibits biotin synthase. ACS Infectious Diseases, 5(4), 598-617. https://doi.org/10.1021/acsinfecdis.8b00345

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

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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.",

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doi = "10.1021/acsinfecdis.8b00345",

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T1 - Investigation of (S)-(-)-acidomycin

T2 - A selective antimycobacterial natural product that inhibits biotin synthase

AU - Bockman, Matthew R.

AU - Engelhart, Curtis A.

AU - Cramer, Julia D.

AU - Howe, Michael D.

AU - Mishra, Neeraj K

AU - Zimmerman, Matthew

AU - Larson, Peter

AU - Alvarez-Cabrera, Nadine

AU - Park, Sae Woong

AU - Boshoff, Helena I.M.

AU - Bean, James M.

AU - Young, Victor G

AU - Ferguson, David M

AU - Dartois, Veronique

AU - Jarrett, Joseph T.

AU - Schnappinger, Dirk

AU - Aldrich, Courtney

N1 - Funding Information: This work was supported by a grant (AI091790 to D.S.) from the National Institutes of Health and in part by the Intramural Research Program of NIAID (AI000693-25). Mass spectrometry was carried out in the Center for Mass Spectrometry and Proteomics, University of Minnesota. Isothermal titration calorimetry was carried out using an ITC-200 microcalorimeter, funded by the NIH Shared Instrumentation Grant S10-OD017982. The Bruker-AXS D8 Venture diffractometer was purchased through a grant from NSF/MRI (#1229400) and the University of Minnesota. We gratefully acknowledge Colin Manoil for supplying A. baumannii AB5075, Ryan Hunter for supplying S. aureus USA300 and P. aeruginosa PA14, and Gary Dunny for suppling E. faecalis V583. We acknowledge the use of the Integrated Genomics Operation Core at MSKCC, funded by the NCI Cancer Center Support Grant (CCSG, P30 CA08748), Cycle for Survival, and the Marie-Joseé and Henry R. Kravis Center for Molecular Oncology. The authors acknowledge the Minnesota Supercomputing Institute (MSI) at the University of Minnesota. Funding Information: This work was supported by a grant (AI091790 to D.S.) from the National Institutes of Health and in part by the Intramural Research Program of NIAID (AI000693-25). Mass spectrometry was carried out in the Center for Mass Spectrometry and Proteomics, University of Minnesota. Isothermal titration calorimetry was carried out using an ITC-200 microcalorimeter, funded by the NIH Shared Instrumentation Grant S10-OD017982. The Bruker-AXS D8 Venture diffractometer was purchased through a grant from NSF/MRI (#1229400) and the University of Minnesota. We gratefully acknowledge Colin Manoil for supplying A. baumannii AB5075, Ryan Hunter for supplying S. aureus USA300 and P. aeruginosa PA14, and Gary Dunny for suppling E. faecalis V583. We acknowledge the use of the Integrated Genomics Operation Core at MSKCC, funded by the NCI Cancer Center Support Grant (CCSG, P30 CA08748), Cycle for Survival, and the Marie-Josei? and Henry R. Kravis Center for Molecular Oncology. The authors acknowledge the Minnesota Supercomputing Institute (MSI) at the University of Minnesota. Funding Information: †Department of Medicinal Chemistry, University of Minnesota, 308 Harvard Street SE, Minneapolis, Minnesota 55455, United States ‡Department of Microbiology and Immunology, Weill Cornell Medical College, 1300 York Avenue, New York, New York 10021, United States §Department of Chemistry, University of Hawaii at Manoa, 2545 McCarthy Mall, Honolulu, Hawaii 96822, United States ∥Public Health Research Institute, Rutgers, The State University of New Jersey, 225 Warren Street, Newark, New Jersey 07103, United States ⊥Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, 5601 Fishers Lane, Bethesda, Maryland 20892, United States #Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, United States ○X-Ray Crystallographic Laboratory, LeClaire-Dow Chemical Instrumentation Facility, Department of Chemistry, University of Minnesota, 207 Pleasant Street SE, Minneapolis, Minnesota 55455, United States Publisher Copyright: © 2019 American Chemical Society.

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Y1 - 2019/4/12

N2 - 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.

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KW - acidomycin

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

Abstract

Bibliographical note

Keywords

UN SDGs

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