Dihydrothiazolo ring-fused 2-pyridone antimicrobial compounds treat Streptococcus pyogenes skin and soft tissue infection

Author:

Zou Zongsen1ORCID,Singh Pardeep2ORCID,Pinkner Jerome S.1ORCID,Obernuefemann Chloe L. P.1,Xu Wei1ORCID,Nye Taylor M.1ORCID,Dodson Karen W.1,Almqvist Fredrik2ORCID,Hultgren Scott J.1ORCID,Caparon Michael G.1ORCID

Affiliation:

1. Department of Molecular Microbiology, Center for Women’s Infectious Disease Research, Washington University School of Medicine, St. Louis, MO 63110, USA.

2. Department of Chemistry, Umeå University, SE-90187 Umeå, Sweden.

Abstract

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.

Publisher

American Association for the Advancement of Science (AAAS)

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