Galbofloxacin: a xenometal-antibiotic with potent in vitro and in vivo efficacy against S. aureus. Issue 43 (25th October 2021)

• Record Type: Journal Article
• Authors: Pandey, Apurva; Śmiłowicz, Dariusz; Boros, Eszter
• Is Part Of: Chemical science. Volume 12:Issue 43(2021)
• Page Start: 14546
• Page End: 14556
• Publication Date: 2021-10-25
• Subjects: Chemistry -- Periodicals; 540.5
• DOI: 10.1039/d1sc04283a
• Languages: English
• ISSNs: 2041-6520

Abstract

Abstract : Galbofloxacin, a novel theranostic xenosiderophore antibiotic, exhibits unparalleled potency in combating S. aureus infections in vivo . 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 67 Galbofloxacin is taken up efficiently using siderophore mediated, active uptake. Biodistribution of 67 Galbofloxacin in a mouse model of intramuscular S. aureus infection revealed renal clearance and enhanced uptake in infected muscle when compared to 67 Ga-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.