title: Acetobixan, an inhibitor of cellulose synthesis identified by microbial bioprospecting.
abstract: In plants, cellulose biosynthesis is an essential process for anisotropic growth and therefore is an ideal target for inhibition. Based on the documented utility of small-molecule inhibitors to dissect complex cellular processes we identified a cellulose biosynthesis inhibitor (CBI), named acetobixan, by bio-prospecting among compounds secreted by endophytic microorganisms. Acetobixan was identified using a drug-gene interaction screen to sift through hundreds of endophytic microbial secretions for one that caused synergistic reduction in root expansion of the leaky AtcesA6prc1-1 mutant. We then mined this microbial secretion for compounds that were differentially abundant compared with Bacilli that failed to mimic CBI action to isolate a lead pharmacophore. Analogs of this lead compound were screened for CBI activity, and the most potent analog was named acetobixan. In living Arabidopsis cells visualized by confocal microscopy, acetobixan treatment caused CESA particles localized at the plasma membrane (PM) to rapidly re-localize to cytoplasmic vesicles. Acetobixan inhibited 14C-Glc uptake into crystalline cellulose. Moreover, cortical microtubule dynamics were not disrupted by acetobixan, suggesting specific activity towards cellulose synthesis. Previous CBI resistant mutants such as ixr1-2, ixr2-1 or aegeus were not cross resistant to acetobixan indicating that acetobixan targets a different aspect of cellulose biosynthesis.
authors.affiliation: Department of Horticulture, University of Kentucky, Lexington, Kentucky, United States of America.
authors.forename: Ye
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Department of Biochemistry and Molecular Biology, Pennsylvania State University, State College, Pennsylvania, United States of America.
authors.forename: Lei
authors.initials: L
authors.lastname: Lei
authors.affiliation: Department of Horticulture, University of Kentucky, Lexington, Kentucky, United States of America.
authors.forename: Chad
authors.initials: C
authors.lastname: Brabham
authors.affiliation: Department of Horticulture, University of Kentucky, Lexington, Kentucky, United States of America.
authors.forename: Jozsef
authors.initials: J
authors.lastname: Stork
authors.affiliation: United State Department of Agriculture Forage-Animal Production Research Unit, University of Kentucky Campus, USDA-ARS, Lexington, Kentucky, United States of America.
authors.forename: James
authors.initials: J
authors.lastname: Strickland
authors.affiliation: Waters Waters Corporation, Milford, Massachusetts, United States of America.
authors.forename: Adam
authors.initials: A
authors.lastname: Ladak
authors.affiliation: Department of Biochemistry and Molecular Biology, Pennsylvania State University, State College, Pennsylvania, United States of America.
authors.forename: Ying
authors.initials: Y
authors.lastname: Gu
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nevada, Reno, Nevada, United States of America.
authors.forename: Ian
authors.initials: I
authors.lastname: Wallace
authors.affiliation: Department of Horticulture, University of Kentucky, Lexington, Kentucky, United States of America.
authors.forename: Seth
authors.initials: S
authors.lastname: DeBolt
mesh_terms: D000081:Acetamides / Q000494:pharmacology*; D001483:Base Sequence; D002482:Cellulose / Q000096:biosynthesis*; D002853:Chromatography, Liquid; D017931:DNA Primers; D013058:Mass Spectrometry; D008829:Microbiology; D018613:Microscopy, Confocal; D012336:RNA, Ribosomal, 16S / Q000235:genetics
chemical_list: D000081:Acetamides; D017931:DNA Primers; C000594472:N-(2-methoxybenzyl)-2-(phenylthio)acetamide; D012336:RNA, Ribosomal, 16S; D002482:Cellulose
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