Issue 43, 2021

Galbofloxacin: a xenometal-antibiotic with potent in vitro and in vivo efficacy against S. aureus

Abstract

Siderophore-antibiotic drug conjugates are considered potent tools to deliver and potentiate the antibacterial activity of antibiotics, but only few have seen preclinical and clinical success. Here, we introduce the gallium(III) complex of a ciprofloxacin-functionalized linear desferrichrome, Galbofloxacin, with a cleavable serine linker as a potent therapeutic for S. aureus bacterial infections. We employed characterization using in vitro inhibitory assays, radiochemical, tracer-based uptake and pharmacokinetic assessment of our lead compound, culminating in in vivo efficacy studies in a soft tissue model of infection. Galbofloxacin exhibits a minimum inhibitory concentration of (MIC98) 93 nM in wt S. aureus, exceeding the potency of the parent antibiotic ciprofloxacin (0.9 μM). Galbofloxacin is a protease substrate that can release the antibiotic payload in the bacterial cytoplasm. Radiochemical experiments with wt bacterial strains reveal that 67Galbofloxacin is taken up efficiently using siderophore mediated, active uptake. Biodistribution of 67Galbofloxacin in a mouse model of intramuscular S. aureus infection revealed renal clearance and enhanced uptake in infected muscle when compared to 67Ga-citrate, which showed no selectivity. A subsequent in vivo drug therapy study reveals efficient reduction in S. aureus infection burden and sustained survival with Galbofloxacin for 7 days. Ciprofloxacin had no treatment efficacy at identical molecular dose (9.3 μmol kg−1) and resulted in death of all study animals in <24 hours. Taken together, the favorable bacterial growth inhibitory, pharmacokinetic and in vivo efficacy properties qualify Galbofloxacin as the first rationally designed Ga-coordination complex for the management of S. aureus bacterial infections.

Graphical abstract: Galbofloxacin: a xenometal-antibiotic with potent in vitro and in vivo efficacy against S. aureus

Supplementary files

Article information

Article type
Edge Article
Submitted
04 aug 2021
Accepted
14 okt 2021
First published
19 okt 2021
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2021,12, 14546-14556

Galbofloxacin: a xenometal-antibiotic with potent in vitro and in vivo efficacy against S. aureus

A. Pandey, D. Śmiłowicz and E. Boros, Chem. Sci., 2021, 12, 14546 DOI: 10.1039/D1SC04283A

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