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Targeting the chromosome partitioning protein ParA in tuberculosis drug discovery

Citation

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]

DOI: doi:10.1093/jac/dkq311

Abstract

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 Details

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 Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Infectious Diseases
Author:O'Toole, RF (Dr Ronan O'Toole)
ID Code:95709
Year Published:2010
Web of Science® Times Cited:19
Deposited By:Medicine (Discipline)
Deposited On:2014-10-07
Last Modified:2014-10-07
Downloads:0

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