title: Activity and Predicted Nephrotoxicity of Synthetic Antibiotics Based on Polymyxin B.
abstract: The polymyxin lipodecapeptides colistin and polymyxin B have become last resort therapies for infections caused by highly drug-resistant Gram-negative bacteria. Unfortunately, their utility is compromised by significant nephrotoxicity and polymyxin-resistant bacterial strains. We have conducted a systematic activity-toxicity investigation by varying eight of the nine polymyxin amino acid free side chains, preparing over 30 analogues using a novel solid-phase synthetic route. Compounds were tested against a panel of Gram-negative bacteria and counter-screened for in vitro cell toxicity. Promising compounds underwent additional testing against primary kidney cells isolated from human kidneys to better predict their nephrotoxic potential. Many of the new compounds possessed equal or better antimicrobial potency compared to polymyxin B, and some were less toxic than polymyxin B and colistin against mammalian HepG2 cells and human primary kidney cells. These initial structure-activity and structure-toxicity studies set the stage for further improvements to the polymyxin class of antibiotics.
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland , Brisbane, Queensland 4072, Australia.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Gallardo-Godoy
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland , Brisbane, Queensland 4072, Australia.
authors.forename: Craig
authors.initials: C
authors.lastname: Muldoon
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland , Brisbane, Queensland 4072, Australia.
authors.forename: Bernd
authors.initials: B
authors.lastname: Becker
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland , Brisbane, Queensland 4072, Australia.
authors.forename: Alysha G
authors.initials: AG
authors.lastname: Elliott
authors.affiliation: Department of Pharmacology, School of Medicine, Wayne State University , 540 East Canfield Avenue, Detroit, Michigan 48201, United States.
authors.forename: Lawrence H
authors.initials: LH
authors.lastname: Lash
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland , Brisbane, Queensland 4072, Australia.
authors.forename: Johnny X
authors.initials: JX
authors.lastname: Huang
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland , Brisbane, Queensland 4072, Australia.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Butler
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland , Brisbane, Queensland 4072, Australia.
authors.forename: Ruby
authors.initials: R
authors.lastname: Pelingon
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland , Brisbane, Queensland 4072, Australia.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Kavanagh
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland , Brisbane, Queensland 4072, Australia.
authors.forename: Soumya
authors.initials: S
authors.lastname: Ramu
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland , Brisbane, Queensland 4072, Australia.
authors.forename: Wanida
authors.initials: W
authors.lastname: Phetsang
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland , Brisbane, Queensland 4072, Australia.
authors.forename: Mark A T
authors.initials: MA
authors.lastname: Blaskovich
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland , Brisbane, Queensland 4072, Australia.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Cooper
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D024881:Drug Resistance, Bacterial / Q000187:drug effects; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D007668:Kidney / Q000187:drug effects*; D007711:Klebsiella pneumoniae / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D008968:Molecular Conformation; D011112:Polymyxin B / Q000031:analogs & derivatives* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D011112:Polymyxin B