Nisa, S and Blokpoel, MCJ and Robertson, BD and Tyndall, JDA and Lun, S and Bishai, WR and O'Toole, RF, Targeting the chromosome partitioning protein ParA in tuberculosis drug discovery, Journal of Antimicrobial Chemotherapy, 65, (11) pp. 2347-2358. ISSN 0305-7453 (2010) [Refereed Article]
OBJECTIVE: To identify inhibitors of the essential chromosome partitioning protein ParA that are active against Mycobacterium tuberculosis.
METHODS: Antisense expression of the parA orthologue MSMEG_6939 was induced on the Mycobacterium smegmatis background. Screening of synthetic chemical libraries was performed to identify compounds with higher anti-mycobacterial activity in the presence of parA antisense. Differentially active compounds were validated for specific inhibition of purified ParA protein from M. tuberculosis (Rv3918c). ParA inhibitors were then characterized for their activity towards M. tuberculosis in vitro.
RESULTS: Under a number of culture conditions, parA antisense expression in M. smegmatis resulted in reduced growth. This effect on growth provided a basis for the detection of compounds that increased susceptibility to expression of parA antisense. Two compounds identified from library screening, phenoxybenzamine and octoclothepin, also inhibited the in vitro ATPase activity of ParA from M. tuberculosis. Structural in silico analyses predict that phenoxybenzamine and octoclothepin undergo interactions compatible with the active site of ParA. Octoclothepin exhibited significant bacteriostatic activity towards M. tuberculosis.
CONCLUSIONS: Our data support the use of whole-cell differential antisense screens for the discovery of inhibitors of specific anti-tubercular drug targets. Using this approach, we have identified an inhibitor of purified ParA and whole cells of M. tuberculosis.
|Item Type:||Refereed Article|
|Keywords:||Antisense; Cell division; Essential gene; Mycobacterium; Tuberculosis|
|Research Division:||Medical and Health Sciences|
|Research Group:||Medical Microbiology|
|Research Field:||Medical Bacteriology|
|Objective Group:||Clinical Health (Organs, Diseases and Abnormal Conditions)|
|Objective Field:||Infectious Diseases|
|Author:||O'Toole, RF (Dr Ronan O'Toole)|
|Web of Science® Times Cited:||21|
|Deposited By:||Medicine (Discipline)|
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