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Screening and Development of New Inhibitors of FtsZ from M-Tuberculosis
Southern Res Inst, Drug Discovery Div, 2000 Ninth Ave South, Birmingham, AL 35205 USA..
Univ Dundee, Coll Life Sci, Drug Discovery Unit, Dundee DD1 5EH, Scotland..
Southern Res Inst, Drug Discovery Div, 2000 Ninth Ave South, Birmingham, AL 35205 USA..
St Jude Childrens Res Hosp, Dept Chem Biol & Therapeut, 262 Danny Thomas Pl, Memphis, TN 38105 USA..
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2016 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 10, e0164100Article in journal (Refereed) Published
Abstract [en]

A variety of commercial analogs and a newer series of Sulindac derivatives were screened for inhibition of M. tuberculosis (Mtb) in vitro and specifically as inhibitors of the essential mycobacterial tubulin homolog, FtsZ. Due to the ease of preparing diverse analogs and a favorable in vivo pharmacokinetic and toxicity profile of a representative analog, the Sulindac scaffold may be useful for further development against Mtb with respect to in vitro bacterial growth inhibition and selective activity for Mtb FtsZ versus mammalian tubulin. Further discovery efforts will require separating reported mammalian cell activity from both antibacterial activity and inhibition of Mtb FtsZ. Modeling studies suggest that these analogs bind in a specific region of the Mtb FtsZ polymer that differs from human tubulin and, in combination with a pharmacophore model presented herein, future hybrid analogs of the reported active molecules that more efficiently bind in this pocket may improve antibacterial activity while improving other drug characteristics.

Place, publisher, year, edition, pages
2016. Vol. 11, no 10, e0164100
National Category
Pharmaceutical Sciences
URN: urn:nbn:se:uu:diva-308919DOI: 10.1371/journal.pone.0164100ISI: 000386205400005PubMedID: 27768711OAI: diva2:1051181
NIH (National Institute of Health), 1 R01 AI50470-01A1 R01 AI48417
Available from: 2016-12-01 Created: 2016-12-01 Last updated: 2016-12-01Bibliographically approved

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Lofton, Hava
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