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Targeting the chromosome partitioning protein ParA in tuberculosis drug discovery

journal contribution
posted on 2023-05-18, 04:14 authored by Nisa, S, Blokpoel, MCJ, Robertson, BD, Tyndall, JDA, Lun, S, Bishai, WR, O'Toole, RF

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.

History

Publication title

Journal of Antimicrobial Chemotherapy

Volume

65

Issue

11

Pagination

2347-2358

ISSN

0305-7453

Department/School

Tasmanian School of Medicine

Publisher

Oxford Univ Press

Place of publication

Great Clarendon St, Oxford, England, Ox2 6Dp

Repository Status

  • Restricted

Socio-economic Objectives

Clinical health not elsewhere classified

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