AI Article Synopsis
- - Bio-AMS is a compound that targets Mycobacterium tuberculosis by blocking key processes needed for its survival, specifically by inhibiting an enzyme called MtBPL involved in biotin utilization.
- - Mtb can become resistant to Bio-AMS through the overproduction of a sulfatase enzyme (Rv3406) which inactivates it, posing a challenge for treatment.
- - Research led to the creation of new analogues that remain effective against Mtb even when Rv3406 is overexpressed, with one derivative (6) showing strong antimycobacterial activity and no signs of resistance development.
Article 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 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 = 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) demonstrating it successfully overcame Rv3406-mediated resistance.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1021/acsinfecdis.8b00038 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Want AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!