title: Screening and Development of New Inhibitors of FtsZ from M. Tuberculosis.
abstract: 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.
authors: Drug Discovery Division, Southern Research Institute, 2000 Ninth Avenue South, Birmingham, Alabama, 35205, United States of America.
authors: Bini
authors: B
authors: Mathew
authors: Drug Discovery Unit, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, United Kingdom.
authors: Judith Varady
authors: http://orcid.org/0000-0002-5399-5625
authors: JV
authors: Hobrath
authors: Drug Discovery Division, Southern Research Institute, 2000 Ninth Avenue South, Birmingham, Alabama, 35205, United States of America.
authors: Larry
authors: L
authors: Ross
authors: Dept. Chemical Biology & Therapeutics, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, United States of America.
authors: Michele C
authors: MC
authors: Connelly
authors: The University of Texas Health Science Center at Tyler, Tyler, Texas, 75708, United States of America.
authors: Hava
authors: H
authors: Lofton
authors: The University of Texas Health Science Center at Tyler, Tyler, Texas, 75708, United States of America.
authors: Malini
authors: M
authors: Rajagopalan
authors: Dept. Chemical Biology & Therapeutics, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, United States of America.
authors: R Kiplin
authors: RK
authors: Guy
authors: Department of Chemistry, The University of Alabama at Birmingham, Birmingham, Alabama, 35294, United States of America.|Division of Hematology and Oncology, The University of Alabama at Birmingham, Birmingham, Alabama, 35294, United States of America.
authors: Robert C
authors: RC
authors: Reynolds
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors*; D051379:Mice; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000378:metabolism*; D013467:Sulindac / Q000494:pharmacology
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D003598:Cytoskeletal Proteins; C071525:FtsZ protein, Bacteria; D013467:Sulindac