Predictive modeling targets thymidylate synthase ThyX in Mycobacterium tuberculosis.
There is an urgent need to identify new treatments for tuberculosis (TB), a major infectious disease caused by Mycobacterium tuberculosis (Mtb), which results in 1.5 million deaths each year. We have targeted two essential enzymes in this organism that are promising for antibacterial therapy and reported to be inhibited by naphthoquinones. ThyX is an essential thymidylate synthase that is mechanistically and structurally unrelated to the human enzyme. DNA gyrase is a DNA topoisomerase present in bacteria and plants but not animals. The current study set out to understand the structure-activity relationships of these targets in Mtb using a combination of cheminformatics and in vitro screening. Here, we report the identification of new Mtb ThyX inhibitors, 2-chloro-3-(4-methanesulfonylpiperazin-1-yl)-1,4-dihydronaphthalene-1,4-dione) and idebenone, which show modest whole-cell activity and appear to act, at least in part, by targeting ThyX in Mtb.
LOB, Ecole polytechnique, CNRS, INSERM, Université Paris-Saclay, 91128 Palaiseau cedex, France.
Kamel
K
Djaout
MRC/NHLS/UCT Molecular Mycobacteriology Research Unit &DST/NRF Centre of Excellence for Biomedical TB Research, Institute of Infectious Diseases and Molecular Medicine and Division of Medical Microbiology, Faculty of Health Sciences, University of Cape Town, AnzioRoad, Observatory 7925, Rondebosch, Cape Town 7700, South Africa.
Vinayak
V
Singh
Epicentre Mbarara Research Centre, Mbarara, Uganda.|Microbiology Department, Faculty of Medicine, Mbarara University of Science and Technology, Mbarara, Uganda.
Yap
Y
Boum
Epicentre Mbarara Research Centre, Mbarara, Uganda.
Victoria
V
Katawera
LOB, Ecole polytechnique, CNRS, INSERM, Université Paris-Saclay, 91128 Palaiseau cedex, France.|Sorbonne Universités, UPMC Univ Paris 06, 4 Place Jussieu, 75005 Paris France.
Hubert F
HF
Becker
Department of Biological Chemistry, John Innes Centre, Norwich Research Park, Norwich NR4 7UH, UK.
Natassja G
NG
Bush
Department of Biological Chemistry, John Innes Centre, Norwich Research Park, Norwich NR4 7UH, UK.
Stephen J
SJ
Hearnshaw
Department of Biological Chemistry, John Innes Centre, Norwich Research Park, Norwich NR4 7UH, UK.
Jennifer E
JE
Pritchard
SRI International, 333 Ravenswood Avenue, Menlo Park, CA 94025, USA.
Pauline
P
Bourbon
SRI International, 333 Ravenswood Avenue, Menlo Park, CA 94025, USA.
Peter B
PB
Madrid
Department of Biological Chemistry, John Innes Centre, Norwich Research Park, Norwich NR4 7UH, UK.
Anthony
A
Maxwell
MRC/NHLS/UCT Molecular Mycobacteriology Research Unit &DST/NRF Centre of Excellence for Biomedical TB Research, Institute of Infectious Diseases and Molecular Medicine and Division of Medical Microbiology, Faculty of Health Sciences, University of Cape Town, AnzioRoad, Observatory 7925, Rondebosch, Cape Town 7700, South Africa.
Valerie
V
Mizrahi
LOB, Ecole polytechnique, CNRS, INSERM, Université Paris-Saclay, 91128 Palaiseau cedex, France.
Hannu
H
Myllykallio
Collaborative Drug Discovery, 1633 Bayshore Highway, Suite 342, Burlingame, CA 94403, USA.|Collaborations in Chemistry, 5616 Hilltop Needmore Road, Fuquay-Varina, NC 27526, USA.
Sean
S
Ekins
D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D001499:Bayes Theorem; D027081:DNA Gyrase / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000032:analysis / Q000737:chemistry / Q000494:pharmacology; D000069550:Machine Learning; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000201:enzymology*; D009285:Naphthoquinones / Q000737:chemistry / Q000494:pharmacology; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D014451:Ubiquinone / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D014584:User-Computer Interface
D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D009285:Naphthoquinones; D014451:Ubiquinone; D013940:Thymidylate Synthase; D027081:DNA Gyrase; C036619:idebenone