title: Inhibitors of bacterial tubulin target bacterial membranesin vivo.
abstract: FtsZ is a homolog of eukaryotic tubulin that is widely conserved among bacteria and coordinates the assembly of the cell division machinery. FtsZ plays a central role in cell replication and is a target of interest for antibiotic development. Several FtsZ inhibitors have been reported. We characterized the mechanism of these compounds in bacteria and found that many of them disrupt the localization of membrane-associated proteins, including FtsZ, by reducing the transmembrane potential or perturbing membrane permeability. We tested whether the reported phenotypes of a broad collection of FtsZ inhibitors disrupt the transmembrane potential inBacillus subtilisstrain 168. Using a combination of flow cytometry and microscopy, we found that zantrin Z1, cinnamaldehyde, totarol, sanguinarine, and viriditoxin decreased theB. subtilistransmembrane potential or perturbed membrane permeability, and influenced the localization of the membrane-associated, division protein MinD. These studies demonstrate that small molecules that disrupt membrane function in bacterial cells produce phenotypes that are similar to the inhibition of proteins associated with membranesin vivo, including bacterial cytoskeleton homologs, such as FtsZ. The results provide a new dimension for consideration in the design and testing of inhibitors of bacterial targets that are membrane-associated and provide additional insight into the structural characteristics of antibiotics that disrupt the membrane.
authors.affiliation: Departments of Biochemistry and Biomedical Engineering, 433 Babcock Drive, Madison, WI 53706, USA. Tel: +1 (608) 890-1342.
authors.forename: Marie H
authors.initials: MH
authors.lastname: Foss
authors.forename: Ye-Jin
authors.initials: YJ
authors.lastname: Eun
authors.forename: Charles I
authors.initials: CI
authors.lastname: Grove
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Pauw
authors.forename: Nohemy A
authors.initials: NA
authors.lastname: Sorto
authors.forename: Jarred W
authors.initials: JW
authors.lastname: Rensvold
authors.forename: David J
authors.initials: DJ
authors.lastname: Pagliarini
authors.forename: Jared T
authors.initials: JT
authors.lastname: Shaw
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Weibel
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