title: A Novel Chemical Biology Approach for Mapping of Polymyxin Lipopeptide Antibody Binding Epitopes.
abstract: Polymyxins B and E (i.e., colistin) are a family of naturally occurring lipopeptide antibiotics that are our last line of defense against multidrug resistant (MDR) Gram-negative pathogens. Unfortunately, nephrotoxicity is a dose-limiting factor for polymyxins that limits their clinical utility. Our recent studies demonstrate that polymyxin-induced nephrotoxicity is a result of their extensive accumulation in renal tubular cells. The design and development of safer, novel polymyxin lipopeptides is hampered by our limited understanding of their complex structure-nephrotoxicity relationships. This is the first study to employ a novel targeted chemical biology approach to map the polymyxin recognition epitope of a commercially available polymyxin mAb and demonstrate its utility for mapping the kidney distribution of a novel, less nephrotoxic polymyxin lipopeptide. Eighteen novel polymyxin lipopeptide analogues were synthesized with modifications in the polymyxin core domains, namely, the N-terminal fatty acyl region, tripeptide linear segment, and cyclic heptapeptide. Surface plasmon resonance epitope mapping revealed that the monoclonal antibody (mAb) recognition epitope consisted of the hydrophobic domain (N-terminal fatty acyl and position 6/7) and diaminobutyric acid (Dab) residues at positions 3, 5, 8, and 9 of the polymyxin molecule. Structural diversity within the hydrophobic domains and Dab 3 position are tolerated. Enlightened with an understating of the structure-binding relationships between the polymyxin mAb and the core polymyxin scaffold, we can now rationally employ the mAb to probe the kidney distribution of novel polymyxin lipopeptides. This information will be vital in the design of novel, safer polymyxins through chemical tailoring of the core scaffold and exploration of the elusive/complex polymyxin structure-nephrotoxicity relationships.
authors.forename: Tony
authors.initials: T
authors.lastname: Velkov
authors.forename: Bo
authors.initials: B
authors.lastname: Yun
authors.forename: Elena K
authors.initials: EK
authors.lastname: Schneider
authors.forename: Mohammad A K
authors.initials: MA
authors.lastname: Azad
authors.affiliation: CSIRO Manufacturing , Parkville, Victoria 3052, Australia.
authors.forename: Olan
authors.initials: O
authors.lastname: Dolezal
authors.forename: Faye C
authors.initials: FC
authors.lastname: Morris
authors.forename: Roger L
authors.initials: RL
authors.lastname: Nation
authors.forename: Jiping
authors.initials: J
authors.lastname: Wang
authors.forename: Ke
authors.initials: K
authors.lastname: Chen
authors.forename: Heidi H
authors.initials: HH
authors.lastname: Yu
authors.forename: Lv
authors.initials: L
authors.lastname: Wang
authors.forename: Philip E
authors.initials: PE
authors.lastname: Thompson
authors.forename: Kade D
authors.initials: KD
authors.lastname: Roberts
authors.forename: Jian
authors.initials: J
authors.lastname: Li
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D000906:Antibodies / Q000737:chemistry; D001419:Bacteria / Q000187:drug effects; D000939:Epitopes / Q000737:chemistry* / Q000494:pharmacology; D057927:Hydrophobic and Hydrophilic Interactions; D007668:Kidney / Q000187:drug effects; D051379:Mice; D011113:Polymyxins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D000906:Antibodies; D000939:Epitopes; D011113:Polymyxins
keywords: chemical biology; epitope mapping; monoclonal antibody; polymyxin