title: Targeted Antibiotic Delivery: Selective Siderophore Conjugation with Daptomycin Confers Potent Activity against Multidrug Resistant Acinetobacter baumannii Both in Vitro and in Vivo.
abstract: In order to address the dire need for new antibiotics to treat specific strains of drug resistant Gram-negative bacterial infections, a mixed ligand analog of the natural Acinetobacter baumannii selective siderophore, fimsbactin, was coupled to daptomycin, a Gram-positive only antibiotic. The resulting conjugate 11 has potent activity against multidrug resistant strains of A. baumannii both in vitro and in vivo. The study also indicates that conjugation of siderophores to "drugs" that are much larger than the siderophore (iron transport agent) itself facilitates active uptake that circumvents the normal permeability problems in Gram-negative bacteria. The results demonstrate the ability to extend activity of a normally Gram-positive only antibiotic to create a potent and targeted Gram-negative antibiotic using a bacterial iron transport based sideromycin Trojan horse strategy.
authors.affiliation: Hsiri Therapeutics , Innovation Park, 1400 East Angela Boulevard, South Bend, Indiana 46617, United States.
authors.forename: Manuka
authors.initials: M
authors.lastname: Ghosh
authors.affiliation: Hsiri Therapeutics , Innovation Park, 1400 East Angela Boulevard, South Bend, Indiana 46617, United States.|Department of Chemistry and Biochemistry, University of Notre Dame , Notre Dame, Indiana 46556, United States.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Miller
authors.affiliation: Hsiri Therapeutics , Innovation Park, 1400 East Angela Boulevard, South Bend, Indiana 46617, United States.
authors.forename: Ute
authors.initials: U
authors.lastname: Möllmann
authors.affiliation: Hsiri Therapeutics, LLC , Rosetree Corporate Center, 1400 N. Providence Road, Building 1, Suite 115S, Media, Pennsylvania 19063, United States.
authors.forename: William D
authors.initials: WD
authors.lastname: Claypool
authors.affiliation: Frieman Life Sciences Center, University of Notre Dame , Notre Dame, Indiana 46556, United States.
authors.forename: Valerie A
authors.initials: VA
authors.lastname: Schroeder
authors.affiliation: Frieman Life Sciences Center, University of Notre Dame , Notre Dame, Indiana 46556, United States.
authors.forename: William R
authors.initials: WR
authors.lastname: Wolter
authors.affiliation: Frieman Life Sciences Center, University of Notre Dame , Notre Dame, Indiana 46556, United States.
authors.forename: Mark
authors.initials: M
authors.lastname: Suckow
authors.affiliation: PracticaChem , 5 Lanyuan Road, Room D-603, Huayuan Industrial Park, Tianjin, 300384, China.
authors.forename: Honglin
authors.initials: H
authors.lastname: Yu
authors.affiliation: PracticaChem , 5 Lanyuan Road, Room D-603, Huayuan Industrial Park, Tianjin, 300384, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Li
authors.affiliation: PracticaChem , 5 Lanyuan Road, Room D-603, Huayuan Industrial Park, Tianjin, 300384, China.
authors.forename: Weiqiang
authors.initials: W
authors.lastname: Huang
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame , Notre Dame, Indiana 46556, United States.
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Zajicek
authors.affiliation: Hsiri Therapeutics , Innovation Park, 1400 East Angela Boulevard, South Bend, Indiana 46617, United States.|Department of Chemistry and Biochemistry, University of Notre Dame , Notre Dame, Indiana 46556, United States.
authors.forename: Marvin J
authors.identifier: 0000-0002-3704-8214
authors.initials: MJ
authors.lastname: Miller
mesh_terms: D040981:Acinetobacter baumannii / Q000187:drug effects*; D017576:Daptomycin / Q000737:chemistry* / Q000494:pharmacology*; D024901:Drug Resistance, Multiple, Bacterial; D006801:Humans; D066298:In Vitro Techniques; D017262:Siderophores / Q000737:chemistry*
chemical_list: D017262:Siderophores; D017576:Daptomycin