Inhibition of MptpB phosphatase from Mycobacterium tuberculosis impairs mycobacterial survival in macrophages.
OBJECTIVE
The secreted Mycobacterium tuberculosis protein tyrosine phosphatase (MptpB) is a virulence factor for M. tuberculosis and contributes to its survival within host macrophages. The aim of this study was to identify potent selective inhibitors of MptpB and to determine the efficacy of these compounds in mycobacterium-infected macrophages.


METHODS
The inhibitory effect of a small library of compounds on MptpB was first examined in vitro. The efficacy of these compounds was further examined in mycobacterium-infected macrophages.


RESULTS
We have identified a new family of double-site isoxazole-based compounds that are potent selective inhibitors of MptpB. Importantly, the inhibitors substantially reduce mycobacterial survival in infected macrophages. In contrast with current anti-tubercular drugs, these MptpB inhibitors do not have bactericidal action but rather, severely impair mycobacterial growth within macrophages. Docking analysis suggests a double-site binding mechanism of inhibition with the isoxazole head in the active site and a salicylate group in a secondary binding pocket that is a unique structural feature of MptpB.


CONCLUSIONS
These results provide the first evidence that inhibition of phosphatases can be exploited against mycobacterial infections. The cell activity of the inhibitors together with the lack of MptpB human orthologues suggests a strong potential for these compounds to be developed as drug candidates against tuberculosis and promises a new therapeutic strategy to tackle clearance and reduce the persistence of M. tuberculosis infection.
Beresford
Nicola J
NJ
University of Manchester, UK.
Mulhearn
Debbie
D
Szczepankiewicz
Bruce
B
Liu
Gang
G
Johnson
Michael E
ME
Fordham-Skelton
Anthony
A
Abad-Zapatero
Cele
C
Cavet
Jennifer S
JS
Tabernero
Lydia
L
D000818:Animals; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D008264:Macrophages / Q000382:microbiology*; D051379:Mice; D050296:Microbial Viability; D008958:Models, Molecular; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology*; D011485:Protein Binding; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*
D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; C414465:MptpA protein, Mycobacterium tuberculosis; D017027:Protein Tyrosine Phosphatases