Identification of Novel Anti-mycobacterial Compounds by Screening a Pharmaceutical Small-Molecule Library against Nonreplicating Mycobacterium tuberculosis.
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.
Department of Microbiology and Immunology, Weill Cornell Medical College , 413 East 69th Street, New York, New York 10021, United States.
Thulasi
T
Warrier
DDW-GlaxoSmithKline , Severo Ochoa 2, Tres Cantos, Madrid 28760, Spain.
Maria
M
Martinez-Hoyos
DDW-GlaxoSmithKline , Severo Ochoa 2, Tres Cantos, Madrid 28760, Spain.
Manuel
M
Marin-Amieva
Department of Computational Chemistry, CIB-GlaxoSmithKline , Severo Ochoa 2, Tres Cantos, Madrid 28760, Spain.
Gonzalo
G
Colmenarejo
DDW-GlaxoSmithKline , Severo Ochoa 2, Tres Cantos, Madrid 28760, Spain.
Esther
E
Porras-De Francisco
DDW-GlaxoSmithKline , Severo Ochoa 2, Tres Cantos, Madrid 28760, Spain.
Ana Isabel
AI
Alvarez-Pedraglio
DDW-GlaxoSmithKline , Severo Ochoa 2, Tres Cantos, Madrid 28760, Spain.
Maria Teresa
MT
Fraile-Gabaldon
DDW-GlaxoSmithKline , Severo Ochoa 2, Tres Cantos, Madrid 28760, Spain.
Pedro Alfonso
PA
Torres-Gomez
Department of Microbiology and Immunology, Weill Cornell Medical College , 413 East 69th Street, New York, New York 10021, United States.
Landys
L
Lopez-Quezada
Department of Microbiology and Immunology, Weill Cornell Medical College , 413 East 69th Street, New York, New York 10021, United States.
Ben
B
Gold
Department of Microbiology and Immunology, Weill Cornell Medical College , 413 East 69th Street, New York, New York 10021, United States.
Julia
J
Roberts
Department of Microbiology and Immunology, Weill Cornell Medical College , 413 East 69th Street, New York, New York 10021, United States.
Yan
Y
Ling
Department of Microbiology and Immunology, Weill Cornell Medical College , 413 East 69th Street, New York, New York 10021, United States.
Selin
S
Somersan-Karakaya
Department of Microbiology and Immunology, Weill Cornell Medical College , 413 East 69th Street, New York, New York 10021, United States.
David
D
Little
DDW-GlaxoSmithKline , Severo Ochoa 2, Tres Cantos, Madrid 28760, Spain.
Nicholas
N
Cammack
Department of Microbiology and Immunology, Weill Cornell Medical College , 413 East 69th Street, New York, New York 10021, United States.
Carl
C
Nathan
DDW-GlaxoSmithKline , Severo Ochoa 2, Tres Cantos, Madrid 28760, Spain.
Alfonso
A
Mendoza-Losana
high-throughput screen; nonreplicating M. tuberculosis; reactive nitrogen species