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

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          Abstract

          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.

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          Most cited references44

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          Hydrolytic stability of hydrazones and oximes.

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            Regulation of virulence determinants in Staphylococcus aureus: complexity and applications.

            The virulence of Staphylococcus aureus is essentially determined by cell wall associated proteins and secreted toxins that are regulated and expressed according to growth phases and/or growth conditions. Gene expression is regulated by specific and sensitive mechanisms, most of which act at the transcriptional level. Regulatory factors constitute numerous complex networks, driving specific interactions with target gene promoters. These factors are largely regulated by two-component regulatory systems, such as the agr, saeRS, srrAB, arlSR and lytRS systems. These systems are sensitive to environmental signals and consist of a sensor histidine kinase and a response regulator protein. DNA-binding proteins, such as SarA and the recently identified SarA homologues (SarR, Rot, SarS, SarT, SarU), also regulate virulence factor expression. These homologues might be intermediates in the regulatory networks. The multiple pathways generated by these factors allow the bacterium to adapt to environmental conditions rapidly and specifically, and to develop infection. Precise knowledge of these regulatory mechanisms and how they control virulence factor expression would open up new perspectives for antimicrobial chemotherapy using key inhibitors of these systems.
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              The lipophilic bullet hits the targets: medicinal chemistry of adamantane derivatives.

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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Antibiotics (Basel)
                Antibiotics (Basel)
                antibiotics
                Antibiotics
                MDPI
                2079-6382
                25 April 2017
                June 2017
                : 6
                : 2
                : 11
                Affiliations
                [1 ]Department of Biomedical Engineering, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA; elc50@ 123456case.edu
                [2 ]Department of Macromolecular Science and Engineering, Case Western Reserve University, 2100 Adelbert Road, Cleveland, OH 44106, USA; jdw114@ 123456case.edu (J.D.W.); jon.pokorski@ 123456case.edu (J.K.P.)
                Author notes
                [* ]Correspondence: horst.vonrecum@ 123456case.edu ; Tel.: +1-216-368-4969; Fax: +1-216-368-5513
                Article
                antibiotics-06-00011
                10.3390/antibiotics6020011
                5485444
                28441360
                668ea180-3af8-4ecd-8e00-6c24f9df55a3
                © 2017 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 14 December 2016
                : 19 April 2017
                Categories
                Article

                erythromycin,infection,ph-sensitive,ph-responsive,hydrophobic,adamantane,cyclodextrin,polymer

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