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

  • ACS Infect Dis. 2018 Jul 13;4(7):1102-1113. doi: 10.1021/acsinfecdis.8b00038.
Matthew R Bockman  1 ,  Curtis A Engelhart  2 ,  Surendra Dawadi  1 ,  Peter Larson  1 ,  Divya Tiwari  2 ,  David M Ferguson  1 ,  Dirk Schnappinger  2 ,  Courtney C Aldrich  1
Affiliations
  • 1. Department of Medicinal Chemistry , University of Minnesota , 308 Harvard Street SE , Minneapolis , Minnesota 55455 , United States.
  • 2. Department of Microbiology and Immunology , Weill Cornell Medical College , 1300 York Avenue , New York , New York 10021 , United States.
PMID: 29663798 DOI: 10.1021/acsinfecdis.8b00038
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.

Keywords
Mycobacterium tuberculosis; adenylation; biotin protein ligase; bisubstrate inhibitor; metabolism; tuberculosis.
Products