Journal
BIOCONJUGATE CHEMISTRY
Volume 30, Issue 3, Pages 751-759Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.bioconjchem.8b00887
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Funding
- Department of Science and Technology (DST) [EMR/2015/000668]
- Department of Biotechnology, India [BT/PR15848/MED/29/1025/2016]
- Council for Scientific and Industrial Research (CSIR)
- Department of Science and Technology Innovation in Science Pursuit for Inspired Research (DST-INSPIRE)
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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.
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