title: Divin: a small molecule inhibitor of bacterial divisome assembly.
abstract: Bacterial cell division involves the dynamic assembly of division proteins and coordinated constriction of the cell envelope. A wide range of factors regulates cell division--including growth and environmental stresses--and the targeting of the division machinery has been a widely discussed approach for antimicrobial therapies. This paper introduces divin, a small molecule inhibitor of bacterial cell division that may facilitate mechanistic studies of this process. Divin disrupts the assembly of late division proteins, reduces peptidoglycan remodeling at the division site, and blocks compartmentalization of the cytoplasm. In contrast to other division inhibitors, divin does not interact with the tubulin homologue FtsZ, affect chromosome segregation, or activate regulatory mechanisms that inhibit cell division indirectly. Our studies of bacterial cell division using divin as a probe suggest that dividing bacteria proceed through several morphological stages of the cell envelope, and FtsZ is required but not sufficient to compartmentalize the cytoplasmic membrane at the division site. Divin is only moderately toxic to mammalian cells at concentrations that inhibit the growth of clinical pathogens. These characteristics make divin a useful probe for studying bacterial cell division and a starting point for the development of new classes of therapeutic agents.
authors.affiliation: Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA.
authors.forename: Ye-Jin
authors.initials: YJ
authors.lastname: Eun
authors.forename: Maoquan
authors.initials: M
authors.lastname: Zhou
authors.forename: Daniela
authors.initials: D
authors.lastname: Kiekebusch
authors.forename: Susan
authors.initials: S
authors.lastname: Schlimpert
authors.forename: Rishi R
authors.initials: RR
authors.lastname: Trivedi
authors.forename: Somenath
authors.initials: S
authors.lastname: Bakshi
authors.forename: Zhou
authors.initials: Z
authors.lastname: Zhong
authors.forename: Taylor A
authors.initials: TA
authors.lastname: Wahlig
authors.forename: Martin
authors.initials: M
authors.lastname: Thanbichler
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Weibel
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology*; D016935:Caulobacter crescentus / Q000166:cytology / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004926:Escherichia coli / Q000166:cytology / Q000187:drug effects*; D006834:Hydrazines / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009281:Naphthalenes / Q000737:chemistry / Q000494:pharmacology*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D001562:Benzimidazoles; D006834:Hydrazines; C586112:N'-((E)-(2-hydroxynaphthalen-1-yl)methylidene)-3-(2-methyl-1H-benzimidazol-1-yl)propanehydrazide; D009281:Naphthalenes; D054852:Small Molecule Libraries