eCite Digital Repository

Targeting the chromosome partitioning protein ParA in tuberculosis drug discovery


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


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:Biomedical and Clinical Sciences
Research Group:Medical microbiology
Research Field:Medical bacteriology
Objective Division:Health
Objective Group:Clinical health
Objective Field:Clinical health not elsewhere classified
UTAS Author:O'Toole, RF (Dr Ronan O'Toole)
ID Code:95709
Year Published:2010
Web of Science® Times Cited:25
Deposited By:Medicine
Deposited On:2014-10-07
Last Modified:2014-10-07

Repository Staff Only: item control page