Fluoroquinolones
(FQs) are among the front-line antibiotics used
to treat severe infections caused by Gram-negative bacteria. However,
recently, due to toxicity concerns, their use has been severely restricted.
Hence, efforts to direct delivery of this antibiotic specifically
to bacteria/site of infection are underway. Here, we report a strategy
that uses a bacterial enzyme for activation of a prodrug to generate
the active antibiotic. The ciprofloxacin-latent fluorophore conjugate 1, which is designed as a substrate for nitroreductase (NTR),
a bacterial enzyme, was synthesized. Upon activation by NTR, release
of Ciprofloxacin (CIP) as well as a fluorescence reporter was observed.
We provide evidence for the prodrug permeating bacteria to generate
a fluorescent signal and we found no evidence for activation in mammalian
cells supporting selectivity of activation within bacteria. As a testament
to its efficacy, 1 was found to have potent bactericidal
activity nearly identical to CIP and significantly reduced the bacterial
burden in a neutropenic mouse thigh infection model, again, at comparable
potency with CIP, a clinically used FQ. Thus, together, we have developed
a small molecule that facilitates bacteria-specific fluoroquinolone
delivery.
A series of cell-permeable esterase-sensitive sulfonates that undergo self-immolation to produce sulfur dioxide (SO), a gaseous pollutant with new and emerging biological roles, is reported. These compounds should facilitate the study SO biology and will lay the platform for newer stimuli-responsive donors of this gas.
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