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

Yukiko Miyamoto, Jarosław Kalisiak, Keith Korthals, Tineke Lauwaet, Dae Young Cheung, Ricardo Lozano, Eduardo R. Cobo, Peter Upcroft, Jacqueline A. Upcroft, Douglas E. Berg, Frances D. Gillin, Valery V. Fokin, K. Barry Sharpless, Lars Eckmann

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)17564-17569
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number43
DOIs
Publication statusPublished - 22 Oct 2013
Externally publishedYes

Keywords

  • Antibiotics
  • Infectious diseases
  • Medicinal chemistry

ASJC Scopus subject areas

  • General

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  • Cite this

    Miyamoto, Y., Kalisiak, J., Korthals, K., Lauwaet, T., Cheung, D. Y., Lozano, R., Cobo, E. R., Upcroft, P., Upcroft, J. A., Berg, D. E., Gillin, F. D., Fokin, V. V., Sharpless, K. B., & Eckmann, L. (2013). Expanded therapeutic potential in activity space of next-generation 5-nitroimidazole antimicrobials with broad structural diversity. Proceedings of the National Academy of Sciences of the United States of America, 110(43), 17564-17569. https://doi.org/10.1073/pnas.1302664110