title: Bacterial Sliding Clamp Inhibitors that Mimic the Sequential Binding Mechanism of Endogenous Linear Motifs.
abstract: The bacterial DNA replication machinery presents new targets for the development of antibiotics acting via novel mechanisms. One such target is the protein-protein interaction between the DNA sliding clamp and the conserved peptide linear motifs in DNA polymerases. We previously established that binding of linear motifs to the Escherichia coli sliding clamp occurs via a sequential mechanism that involves two subsites (I and II). Here, we report the development of small-molecule inhibitors that mimic this mechanism. The compounds contain tetrahydrocarbazole moieties as "anchors" to occupy subsite I. Functional groups appended at the tetrahydrocarbazole nitrogen bind to a channel gated by the side chain of M362 and lie at the edge of subsite II. One derivative induced the formation of a new binding pocket, termed subsite III, by rearrangement of a loop adjacent to subsite I. Discovery of the extended binding area will guide further inhibitor development.
authors.affiliation: †School of Chemistry and Centre for Medical and Molecular Bioscience, The University of Wollongong and The Illawarra Health and Medical Research Institute, Wollongong, New South Wales 2522, Australia.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Yin
authors.affiliation: †School of Chemistry and Centre for Medical and Molecular Bioscience, The University of Wollongong and The Illawarra Health and Medical Research Institute, Wollongong, New South Wales 2522, Australia.
authors.forename: Louise R
authors.initials: LR
authors.lastname: Whittell
authors.affiliation: †School of Chemistry and Centre for Medical and Molecular Bioscience, The University of Wollongong and The Illawarra Health and Medical Research Institute, Wollongong, New South Wales 2522, Australia.
authors.forename: Yao
authors.initials: Y
authors.lastname: Wang
authors.affiliation: †School of Chemistry and Centre for Medical and Molecular Bioscience, The University of Wollongong and The Illawarra Health and Medical Research Institute, Wollongong, New South Wales 2522, Australia.
authors.forename: Slobodan
authors.initials: S
authors.lastname: Jergic
authors.affiliation: ‡School of Environmental and Life Sciences, The University of Newcastle, Callaghan, New South Wales 2308, Australia.
authors.forename: Cong
authors.initials: C
authors.lastname: Ma
authors.affiliation: ‡School of Environmental and Life Sciences, The University of Newcastle, Callaghan, New South Wales 2308, Australia.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Lewis
authors.affiliation: †School of Chemistry and Centre for Medical and Molecular Bioscience, The University of Wollongong and The Illawarra Health and Medical Research Institute, Wollongong, New South Wales 2522, Australia.
authors.forename: Nicholas E
authors.initials: NE
authors.lastname: Dixon
authors.affiliation: †School of Chemistry and Centre for Medical and Molecular Bioscience, The University of Wollongong and The Illawarra Health and Medical Research Institute, Wollongong, New South Wales 2522, Australia.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Beck
authors.affiliation: †School of Chemistry and Centre for Medical and Molecular Bioscience, The University of Wollongong and The Illawarra Health and Medical Research Institute, Wollongong, New South Wales 2522, Australia.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Kelso
authors.affiliation: †School of Chemistry and Centre for Medical and Molecular Bioscience, The University of Wollongong and The Illawarra Health and Medical Research Institute, Wollongong, New South Wales 2522, Australia.
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Oakley
mesh_terms: D020816:Amino Acid Motifs; D001665:Binding Sites; D002227:Carbazoles / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004261:DNA Replication; D004269:DNA, Bacterial / Q000378:metabolism; D004259:DNA-Directed DNA Polymerase / Q000737:chemistry; D004926:Escherichia coli / Q000254:growth & development / Q000378:metabolism*; D029968:Escherichia coli Proteins / Q000737:chemistry* / Q000378:metabolism*; D005454:Fluorescence Polarization; D006860:Hydrogen Bonding; D008958:Models, Molecular; D018716:Molecular Mimicry; D015394:Molecular Structure; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013499:Surface Properties; D013816:Thermodynamics
chemical_list: D002227:Carbazoles; D004269:DNA, Bacterial; D029968:Escherichia coli Proteins; D004259:DNA-Directed DNA Polymerase