Expanded therapeutic potential in activity space of next-generation 5-nitroimidazole antimicrobials with broad structural diversity

Metronidazole and other 5-nitroimidazoles (5-NI) are among the most effective antimicrobials available against many important anaerobic pathogens, but evolving resistance is threatening their long-term clinical utility. The common 5-NIs were developed decades ago, yet little 5-NI drug development ha...

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Veröffentlicht in:Proceedings of the National Academy of Sciences - PNAS 2013-10, Vol.110 (43), p.17564-17569
Hauptverfasser: Miyamoto, Yukiko, Kalisiak, Jarosław, Korthals, Keith, Lauwaet, Tineke, Cheung, Dae Young, Lozano, Ricardo, Cobo, Eduardo R., Upcroft, Peter, Upcroft, Jacqueline A., Berg, Douglas E., Gillin, Frances D., Fokin, Valery V., Sharpless, K. Barry, Eckmann, Lars
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Sprache:eng
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Zusammenfassung:Metronidazole and other 5-nitroimidazoles (5-NI) are among the most effective antimicrobials available against many important anaerobic pathogens, but evolving resistance is threatening their long-term clinical utility. The common 5-NIs were developed decades ago, yet little 5-NI drug development has since taken place, leaving the true potential of this important drug class unexplored. Here we report on a unique approach to the modular synthesis of diversified 5-NIs for broad exploration of their antimicrobial potential. Many of the more than 650 synthesized compounds, carrying structurally diverse functional groups, have vastly improved activity against a range of microbes, including the pathogenic protozoa Giardia lamblia and Trichomonas vaginalis , and the bacterial pathogens Helicobacter pylori, Clostridium difficile , and Bacteroides fragilis . Furthermore, they can overcome different forms of drug resistance, and are active and nontoxic in animal infection models. These findings provide impetus to the development of structurally diverse, next-generation 5-NI drugs as agents in the antimicrobial armamentarium, thus ensuring their future viability as primary therapeutic agents against many clinically important infections.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1302664110