Open AccessIdentification of Novel Anti-mycobacterial Compounds by Screening a Pharmaceutical Small-Molecule Library against Nonreplicating Mycobacterium tuberculosis
Author(s) -
Thulasi Warrier,
María Martínez-Hoyos,
Manuel Marin-Amieva,
Gonzalo Colmenarejo,
Esther Porras-De Francisco,
Ana Isabel Alvarez-Pedraglio,
María Teresa Fraile-Gabaldón,
P.A. Torres,
Landys Lopez Quezada,
Ben Gold,
Julia Roberts,
Yan Lv,
Selin Somersan-Karakaya,
David Little,
N. Cammack,
Carl Nathan,
Alfonso Mendoza-Losana
Publication year - 2015
Publication title -
acs infectious diseases
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.324
H-Index - 39
ISSN - 2373-8227
DOI - 10.1021/acsinfecdis.5b00025
Subject(s) - mycobacterium tuberculosis , tuberculosis , cytotoxicity , in vitro , microbiology and biotechnology , biology , potency , mycobacterium , chemistry , computational biology , biochemistry , medicine , pathology
Identification of compounds that target metabolically diverse subpopulations of Mycobacterium tuberculosis (Mtb) may contribute to shortening the course of treatment for tuberculosis. This study screened 270,000 compounds from GlaxoSmithKline's collection against Mtb in a nonreplicating (NR) state imposed in vitro by a combination of four host-relevant stresses. Evaluation of 166 confirmed hits led to detailed characterization of 19 compounds for potency, specificity, cytotoxicity, and stability. Compounds representing five scaffolds depended on reactive nitrogen species for selective activity against NR Mtb, and two were stable in the assay conditions. Four novel scaffolds with activity against replicating (R) Mtb were also identified. However, none of the 19 compounds was active against Mtb in both NR and R states. There was minimal overlap between compounds found active against NR Mtb and those previously identified as active against R Mtb, supporting the hypothesis that NR Mtb depends on distinct metabolic pathways for survival.