Targeted Antibiotic Delivery: Selective Siderophore Conjugation with Daptomycin Confers Potent Activity against Multidrug Resistant Acinetobacter baumannii Both in Vitro and in Vivo

Manuka Ghosh, Patricia A. Miller, Ute Möllmann, William D. Claypool, Valerie A. Schroeder, William R. Wolter, Mark Suckow, Honglin Yu, Shuang Li, Weiqiang Huang, Jaroslav Zajicek, Marvin J. Miller

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)4577-4583
Number of pages7
JournalJournal of medicinal chemistry
Volume60
Issue number11
DOIs
StatePublished - Jun 8 2017

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