Journal
TUBERCULOSIS
Volume 91, Issue 4, Pages 277-286Publisher
CHURCHILL LIVINGSTONE
DOI: 10.1016/j.tube.2011.03.005
Keywords
Mycobacterium tuberculosis; Kinases; PknB; Inhibitors
Categories
Funding
- MRC Technology [A853-0058]
- Medical Research Council [U117585867, U117584228]
- MRC [MC_U117584228, MC_U117585867, MC_G1000806] Funding Source: UKRI
- Medical Research Council [MC_U117585867, MC_U117584228, MC_G1000806] Funding Source: researchfish
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PknB is an essential serine/threonine kinase of Mycobacterium tuberculosis with possible roles in a number of signalling pathways involved in cell division and metabolism. We screened a library of >50,000 compounds for inhibitors of the in vitro phosphorylation of GarA (Rv1827) by PknB and identified a number of inhibitors. A program of synthetic medicinal chemistry was subsequently conducted around one class of inhibitors and was successful in generating ATP competitive inhibitors with potency in the nanomolar range. Compounds in this class showed cross-reactivity with the related M. tuberculosis kinase, PknF, but not with PknG in an in vitro autophosphorylation assay. These synthesised inhibitors were able to prevent the growth of M. tuberculosis in an Alamar blue assay and in an intracellular model of infection, but only in the micromolar range. We attempted to determine if cell wall permeability was an explanation for the discrepancy between the potent in vitro compared with relatively poor in vivo activity, but found no evidence that the activity of the inhibitors could be improved by weakening the cell wall. Despite a number of drug discovery efforts attempting to develop inhibitors against PknB, it is yet to be reported that any such inhibitors prevent mycobacterial growth at submicromolar concentrations. (C) 2011 Elsevier Ltd. All rights reserved.
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