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 language | English |
|---|---|
| Pages (from-to) | 17564-17569 |
| Number of pages | 6 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 110 |
| Issue number | 43 |
| DOIs | |
| Publication status | Published - 22 Oct 2013 |
| Externally published | Yes |
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Keywords
- Antibiotics
- Infectious diseases
- Medicinal chemistry
ASJC Scopus subject areas
- General
Cite this
Expanded therapeutic potential in activity space of next-generation 5-nitroimidazole antimicrobials with broad structural diversity. / 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.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 110, No. 43, 22.10.2013, p. 17564-17569.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Expanded therapeutic potential in activity space of next-generation 5-nitroimidazole antimicrobials with broad structural diversity
AU - Miyamoto, Yukiko
AU - Kalisiak, Jarosław
AU - Korthals, Keith
AU - Lauwaet, Tineke
AU - Cheung, Dae Young
AU - Lozano, Ricardo
AU - Cobo, Eduardo R.
AU - Upcroft, Peter
AU - Upcroft, Jacqueline A.
AU - Berg, Douglas E.
AU - Gillin, Frances D.
AU - Fokin, Valery V.
AU - Sharpless, K. Barry
AU - Eckmann, Lars
PY - 2013/10/22
Y1 - 2013/10/22
N2 - 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.
AB - 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.
KW - Antibiotics
KW - Infectious diseases
KW - Medicinal chemistry
UR - http://www.scopus.com/inward/record.url?scp=84886416314&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84886416314&partnerID=8YFLogxK
U2 - 10.1073/pnas.1302664110
DO - 10.1073/pnas.1302664110
M3 - Article
VL - 110
SP - 17564
EP - 17569
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 43
ER -