Targeting the chromosome partitioning protein ParA in tuberculosis drug discovery.

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dc.citation.issue11
dc.citation.volume65
dc.contributor.authorNisa S
dc.contributor.authorBlokpoel MCJ
dc.contributor.authorRobertson BD
dc.contributor.authorTyndall JDA
dc.contributor.authorLun S
dc.contributor.authorBishai WR
dc.contributor.authorO'Toole R
dc.date.available2010-11
dc.date.issued2010-11
dc.descriptionCAUL read and publish agreement 2022
dc.description.abstractOBJECTIVE: 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.
dc.description.publication-statusPublished
dc.format.extent2347 - 2358
dc.identifierhttp://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000282751700011&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=c5bb3b2499afac691c2e3c1a83ef6fef
dc.identifier.citationJOURNAL OF ANTIMICROBIAL CHEMOTHERAPY, 2010, 65 (11), pp. 2347 - 2358
dc.identifier.doi10.1093/jac/dkq311
dc.identifier.eissn1460-2091
dc.identifier.elements-id451869
dc.identifier.harvestedMassey_Dark
dc.identifier.issn0305-7453
dc.relation.isPartOfJOURNAL OF ANTIMICROBIAL CHEMOTHERAPY
dc.subjectMycobacterium
dc.subjecttuberculosis
dc.subjectessential gene
dc.subjectcell division
dc.subjectantisense
dc.subject.anzsrc0605 Microbiology
dc.subject.anzsrc1108 Medical Microbiology
dc.subject.anzsrc1115 Pharmacology and Pharmaceutical Sciences
dc.titleTargeting the chromosome partitioning protein ParA in tuberculosis drug discovery.
dc.typeJournal article
pubs.notesNot known
pubs.organisational-group/Massey University
pubs.organisational-group/Massey University/College of Sciences
pubs.organisational-group/Massey University/College of Sciences/School of Veterinary Science
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