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

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1102-1113
Number of pages12
JournalACS Infectious Diseases
Volume4
Issue number7
DOIs
StatePublished - Jul 13 2018

Fingerprint

Mycobacterium tuberculosis
Nucleosides
Anti-Bacterial Agents
Ligases
Biotin
Sulfatases
Proteins
Microbial Sensitivity Tests
Fatty Acids
Lipids

Keywords

  • Mycobacterium tuberculosis
  • adenylation
  • biotin protein ligase
  • bisubstrate inhibitor
  • metabolism
  • tuberculosis

PubMed: MeSH publication types

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

Cite this

Avoiding Antibiotic Inactivation in Mycobacterium tuberculosis by Rv3406 through Strategic Nucleoside Modification. / Bockman, Matthew R.; Engelhart, Curtis A.; Dawadi, Surendra; Larson, Peter; Tiwari, Divya; Ferguson, David M.; Schnappinger, Dirk; Aldrich, Courtney C.

In: ACS Infectious Diseases, Vol. 4, No. 7, 13.07.2018, p. 1102-1113.

Research output: Contribution to journalArticle

Bockman, Matthew R. ; Engelhart, Curtis A. ; Dawadi, Surendra ; Larson, Peter ; Tiwari, Divya ; Ferguson, David M. ; Schnappinger, Dirk ; Aldrich, Courtney C. / Avoiding Antibiotic Inactivation in Mycobacterium tuberculosis by Rv3406 through Strategic Nucleoside Modification. In: ACS Infectious Diseases. 2018 ; Vol. 4, No. 7. pp. 1102-1113.
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