title: Probing the penetration of antimicrobial polymyxin lipopeptides into gram-negative bacteria.
abstract: The dry antibiotic development pipeline coupled with the emergence of multidrug resistant Gram-negative 'superbugs' has driven the revival of the polymyxin lipopeptide antibiotics. Polymyxin resistance implies a total lack of antibiotics for the treatment of life-threatening infections. The lack of molecular imaging probes that possess native polymyxin-like antibacterial activity is a barrier to understanding the resistance mechanisms and the development of a new generation of polymyxin lipopeptides. Here we report the regioselective modification of the polymyxin B core scaffold at the N-terminus with the dansyl fluorophore to generate an active probe that mimics polymyxin B pharmacologically. Time-lapse laser scanning confocal microscopy imaging of the penetration of probe (1) into Gram-negative bacterial cells revealed that the probe initially accumulates in the outer membrane and subsequently penetrates into the inner membrane and finally the cytoplasm. The implementation of this polymyxin-mimetic probe will advance the development of platforms for the discovery of novel polymyxin lipopeptides with efficacy against polymyxin-resistant strains.
authors.affiliation: Drug Delivery, Disposition and Dynamics and §Department of Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University , Melbourne, Victoria 3800, Australia.
authors.forename: Zakuan Z
authors.initials: ZZ
authors.lastname: Deris
authors.forename: James D
authors.initials: JD
authors.lastname: Swarbrick
authors.forename: Kade D
authors.initials: KD
authors.lastname: Roberts
authors.forename: Mohammad A K
authors.initials: MA
authors.lastname: Azad
authors.forename: Jesmin
authors.initials: J
authors.lastname: Akter
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Horne
authors.forename: Roger L
authors.initials: RL
authors.lastname: Nation
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Rogers
authors.forename: Phillip E
authors.initials: PE
authors.lastname: Thompson
authors.forename: Tony
authors.initials: T
authors.lastname: Velkov
authors.forename: Jian
authors.initials: J
authors.lastname: Li
mesh_terms: D040981:Acinetobacter baumannii / Q000166:cytology / Q000187:drug effects / Q000254:growth & development; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D015195:Drug Design; D024881:Drug Resistance, Bacterial; D006090:Gram-Negative Bacteria / Q000166:cytology / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism*; D007711:Klebsiella pneumoniae / Q000166:cytology / Q000187:drug effects / Q000254:growth & development; D008826:Microbial Sensitivity Tests; D008854:Microscopy, Electron; D008958:Models, Molecular; D008968:Molecular Conformation; D057054:Molecular Imaging; D011112:Polymyxin B / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D011550:Pseudomonas aeruginosa / Q000166:cytology / Q000187:drug effects / Q000254:growth & development
chemical_list: D000900:Anti-Bacterial Agents; D011112:Polymyxin B