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Antibiotics 2017, 6(2), 11;

Erythromycin Modification That Improves Its Acidic Stability while Optimizing It for Local Drug Delivery

Department of Biomedical Engineering, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA
Department of Macromolecular Science and Engineering, Case Western Reserve University, 2100 Adelbert Road, Cleveland, OH 44106, USA
Author to whom correspondence should be addressed.
Academic Editor: Naresh Kumar
Received: 14 December 2016 / Revised: 2 March 2017 / Accepted: 19 April 2017 / Published: 25 April 2017
(This article belongs to the Special Issue Antibiotic Synthesis)
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The antibiotic erythromycin has limited efficacy and bioavailability due to its instability and conversion under acidic conditions via an intramolecular dehydration reaction. To improve the stability of erythromycin, several analogs have been developed—such as azithromycin and clarithromycin—which decrease the rate of intramolecular dehydration. We set out to build upon this prior work by developing a conjugate of erythromycin with improved pH stability, bioavailability, and preferential release from a drug delivery system directly at the low pH of an infection site. To develop this new drug conjugate, adamantane-1-carbohydrazide was covalently attached to erythromycin via a pH-degradable hydrazone bond. Since Staphylococcus aureus infection sites are slightly acidic, the hydrazone bond will undergo hydrolysis liberating erythromycin directly at the infection site. The adamantane group provides interaction with the drug delivery system. This local delivery strategy has the potential of reducing off-target and systemic side-effects. This work demonstrates the synthesis of a pH-cleavable, erythromycin conjugate that retains the inherent antimicrobial activity of erythromycin, has an increased hydrophobicity, and improved stability in acidic conditions; thereby enhancing erythromycin’s bioavailability while simultaneously reducing its toxicity. View Full-Text
Keywords: erythromycin; infection; pH-sensitive; pH-responsive; hydrophobic; adamantane; cyclodextrin; polymer erythromycin; infection; pH-sensitive; pH-responsive; hydrophobic; adamantane; cyclodextrin; polymer

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Cyphert, E.L.; Wallat, J.D.; Pokorski, J.K.; von Recum, H.A. Erythromycin Modification That Improves Its Acidic Stability while Optimizing It for Local Drug Delivery. Antibiotics 2017, 6, 11.

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