Avoiding Antibiotic Inactivation in Mycobacterium tuberculosis by Rv3406 through Strategic Nucleoside Modification

Matthew R. Bockman; Curtis A. Engelhart; Surendra Dawadi; Peter Larson; Divya Tiwari; David M. Ferguson; Dirk Schnappinger; Courtney C. Aldrich

doi:10.1021/acsinfecdis.8b00038

Avoiding Antibiotic Inactivation in Mycobacterium tuberculosis by Rv3406 through Strategic Nucleoside Modification

Matthew R. Bockman, Curtis A. Engelhart, Surendra Dawadi, Peter Larson, Divya Tiwari, David M. Ferguson, Dirk Schnappinger, Courtney C. Aldrich

Medicinal Chemistry

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13 Scopus citations

Abstract

5′-[N-(d-biotinoyl)sulfamoyl]amino-5′-deoxyadenosine (Bio-AMS, 1) possesses selective activity against Mycobacterium tuberculosis (Mtb) and arrests fatty acid and lipid biosynthesis through inhibition of the Mycobacterium tuberculosis biotin protein ligase (MtBPL). Mtb develops spontaneous resistance to 1 with a frequency of at least 1 × 10^-7 by overexpression of Rv3406, a type II sulfatase that enzymatically inactivates 1. In an effort to circumvent this resistance mechanism, we describe herein strategic modification of the nucleoside at the 5′-position to prevent enzymatic inactivation. The new analogues retained subnanomolar potency to MtBPL (K_D = 0.66-0.97 nM), and 5′R-C-methyl derivative 6 exhibited identical antimycobacterial activity toward: Mtb H37Rv, MtBPL overexpression, and an isogenic Rv3406 overexpression strain (minimum inhibitory concentration, MIC = 1.56 μM). Moreover, 6 was not metabolized by recombinant Rv3406 and resistant mutants to 6 could not be isolated (frequency of resistance <1.4 × 10^-10) demonstrating it successfully overcame Rv3406-mediated resistance.

Original language	English (US)
Pages (from-to)	1102-1113
Number of pages	12
Journal	ACS Infectious Diseases
Volume	4
Issue number	7
DOIs	https://doi.org/10.1021/acsinfecdis.8b00038
State	Published - Jul 13 2018

Bibliographical note

Funding Information:
This work was supported by a grant (AI091790 to D.S.) from the National Institutes of Health as well as the University of Minnesota Bighley Fellowship. Isothermal titration calorimetry was carried out using an ITC-200 microcalorimeter, funded by the NIH Shared Instrumentation Grant S10-OD017982. Mass spectrometry was carried out in the Center for Mass Spectrometry and Proteomics, University of Minnesota. We also gratefully acknowledge Bruce Witthuhn for his contributions and assistance using the LC-MS/MS instruments. We also thank Carolyn Bertozzi for providing the Rv3406 over-expression plasmid. Finally, we acknowledge the Minnesota Supercomputing Institute (MSI) at the University of Minnesota for providing resources that contributed to the research results reported within this paper (http://www.msi.umn.edu).

Publisher Copyright:
Copyright © 2018 American Chemical Society.

Keywords

Mycobacterium tuberculosis
adenylation
biotin protein ligase
bisubstrate inhibitor
metabolism
tuberculosis

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title = "Avoiding Antibiotic Inactivation in Mycobacterium tuberculosis by Rv3406 through Strategic Nucleoside Modification",

abstract = "5′-[N-(d-biotinoyl)sulfamoyl]amino-5′-deoxyadenosine (Bio-AMS, 1) possesses selective activity against Mycobacterium tuberculosis (Mtb) and arrests fatty acid and lipid biosynthesis through inhibition of the Mycobacterium tuberculosis biotin protein ligase (MtBPL). Mtb develops spontaneous resistance to 1 with a frequency of at least 1 × 10-7 by overexpression of Rv3406, a type II sulfatase that enzymatically inactivates 1. In an effort to circumvent this resistance mechanism, we describe herein strategic modification of the nucleoside at the 5′-position to prevent enzymatic inactivation. The new analogues retained subnanomolar potency to MtBPL (KD = 0.66-0.97 nM), and 5′R-C-methyl derivative 6 exhibited identical antimycobacterial activity toward: Mtb H37Rv, MtBPL overexpression, and an isogenic Rv3406 overexpression strain (minimum inhibitory concentration, MIC = 1.56 μM). Moreover, 6 was not metabolized by recombinant Rv3406 and resistant mutants to 6 could not be isolated (frequency of resistance <1.4 × 10-10) demonstrating it successfully overcame Rv3406-mediated resistance.",

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note = "Funding Information: This work was supported by a grant (AI091790 to D.S.) from the National Institutes of Health as well as the University of Minnesota Bighley Fellowship. Isothermal titration calorimetry was carried out using an ITC-200 microcalorimeter, funded by the NIH Shared Instrumentation Grant S10-OD017982. Mass spectrometry was carried out in the Center for Mass Spectrometry and Proteomics, University of Minnesota. We also gratefully acknowledge Bruce Witthuhn for his contributions and assistance using the LC-MS/MS instruments. We also thank Carolyn Bertozzi for providing the Rv3406 over-expression plasmid. Finally, we acknowledge the Minnesota Supercomputing Institute (MSI) at the University of Minnesota for providing resources that contributed to the research results reported within this paper (http://www.msi.umn.edu). Publisher Copyright: Copyright {\textcopyright} 2018 American Chemical Society.",

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Avoiding Antibiotic Inactivation in Mycobacterium tuberculosis by Rv3406 through Strategic Nucleoside Modification

Abstract

Bibliographical note

Keywords

UN SDGs

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