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Dihydrothiazolo ring-fused 2-pyridone antimicrobial compounds treat Streptococcus pyogenes skin and soft tissue infection
Department of Molecular Microbiology, Center for Women's Infectious Disease Research, Washington University School of Medicine, St. Louis, United States.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Department of Molecular Microbiology, Center for Women's Infectious Disease Research, Washington University School of Medicine, St. Louis, United States.
Department of Molecular Microbiology, Center for Women's Infectious Disease Research, Washington University School of Medicine, St. Louis, United States.
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2024 (English)In: Science Advances, E-ISSN 2375-2548, Vol. 10, no 31, article id eadn7979Article in journal (Refereed) Published
Abstract [en]

We have developed GmPcides from a peptidomimetic dihydrothiazolo ring-fused 2-pyridone scaffold that has antimicrobial activities against a broad spectrum of Gram-positive pathogens. Here, we examine the treatment efficacy of GmPcides using skin and soft tissue infection (SSTI) and biofilm formation models by Streptococcus pyogenes. Screening our compound library for minimal inhibitory (MIC) and minimal bactericidal (MBC) concentrations identified GmPcide PS757 as highly active against S. pyogenes. Treatment of S. pyogenes biofilm with PS757 revealed robust efficacy against all phases of biofilm formation by preventing initial biofilm development, ceasing biofilm maturation and eradicating mature biofilm. In a murine model of S. pyogenes SSTI, subcutaneous delivery of PS757 resulted in reduced levels of tissue damage, decreased bacterial burdens, and accelerated rates of wound healing, which were associated with down-regulation of key virulence factors, including M protein and the SpeB cysteine protease. These data demonstrate that GmPcides show considerable promise for treating S. pyogenes infections.

Place, publisher, year, edition, pages
American Association for the Advancement of Science (AAAS), 2024. Vol. 10, no 31, article id eadn7979
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Infectious Medicine
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URN: urn:nbn:se:umu:diva-228387DOI: 10.1126/sciadv.adn7979PubMedID: 39093975Scopus ID: 2-s2.0-85200529192OAI: oai:DiVA.org:umu-228387DiVA, id: diva2:1890290
Funder
NIH (National Institutes of Health), RO1dK51406NIH (National Institutes of Health), R01Ai134847-01A1NIH (National Institutes of Health), 1U19Ai157797-01NIH (National Institutes of Health), R21Ai163825Swedish Research Council, 2018-04589Swedish Research Council, 2021-05040The Kempe Foundations, SMK- 1755Familjen Erling-Perssons StiftelseAvailable from: 2024-08-19 Created: 2024-08-19 Last updated: 2024-08-19Bibliographically approved

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Singh, PardeepAlmqvist, Fredrik

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