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extra sugar on vancomycin: new analogues for combating multidrug-resistant staphylococcus aureus and vancomycin-resistant enterococci
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نویسنده
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guan d. ,chen f. ,xiong l. ,tang f. ,faridoon cas ,qiu y. ,zhang n. ,gong l. ,li j. ,lan l. ,huang w.
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منبع
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journal of medicinal chemistry - 2018 - دوره : 61 - شماره : 1 - صفحه:286 -304
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چکیده
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Lipophilic substitution on vancomycin is an effective strategy for the development of novel vancomycin analogues against drug-resistant bacteria by enhancing bacterial cell wall interactions. however, hydrophobic structures usually lead to long elimination half-life and accumulative toxicity; therefore, hydrophilic fragments were also introduced to the lipo-vancomycin to regulate their pharmacokinetic/pharmacodynamic properties. here, we synthesized a series of new vancomycin analogues carrying various sugar moieties on the seventh-amino acid phenyl ring and lipophilic substitutions on vancosamine with extensive structure-activity relationship analysis. the optimal analogues indicated 128-1024-fold higher activity against methicillin-susceptible s. aureus, vancomycin-intermediate resistant s. aureus (visa), and vancomycin-resistant enterococci (vre) compared with that of vancomycin. in vivo pharmacokinetics studies demonstrated the effective regulation of extra sugar motifs, which shortened the half-life and addressed concerns of accumulative toxicity of lipo-vancomycin. this work presents an effective strategy for lipo-vancomycin derivative design by introducing extra sugars, which leads to better antibiotic-like properties of enhanced efficacy, optimal pharmacokinetics, and lower toxicity.
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آدرس
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university of chinese academy of sciences, cas center for excellence in molecular cell science, shanghai institute of materia medica, chinese academy of sciences, key laboratory of receptor research, china, chinese academy of sciences, cas center for excellence in molecular cell science, shanghai institute of materia medica, key laboratory of receptor research, china, east china university of science and technology, cas center for excellence in molecular cell science, shanghai institute of materia medica, chinese academy of sciences, 555 zuchongzhi road, pudong, shanghai, 201203, china, shanghai key laboratory of new drug design, school of pharmacy, shanghai key laboratory of new drug design, china, university of chinese academy of sciences, cas center for excellence in molecular cell science, shanghai institute of materia medica, key laboratory of receptor research, china, chinese academy of sciences, cas center for excellence in molecular cell science, shanghai institute of materia medica, key laboratory of receptor research, china, university of chinese academy of sciences, cas center for excellence in molecular cell science, shanghai institute of materia medica, key laboratory of receptor research, china, university of chinese academy of sciences, cas center for excellence in molecular cell science, shanghai institute of materia medica, key laboratory of receptor research, china, university of chinese academy of sciences, cas center for excellence in molecular cell science, shanghai institute of materia medica, key laboratory of receptor research, china, east china university of science and technology, school of pharmacy, shanghai key laboratory of new drug design, china, university of chinese academy of sciences, cas center for excellence in molecular cell science, shanghai institute of materia medica, state key laboratory of drug research, china, university of chinese academy of sciences, center for bio-drug development, shanghai institute of materia medica, key laboratory of receptor research, china
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Authors
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