Zou Zongsen, Obernuefemann Chloe L P, Singh Pardeep, Pinkner Jerome S, Xu Wei, Nye Taylor M, Dodson Karen W, Almqvist Fredrik, Hultgren Scott J, Caparon Michael G
Department of Molecular Microbiology, Center for Women's Infectious Disease Research, Washington University School of Medicine, St. Louis, Missouri 63110, United States.
Department of Chemistry, Umeå University, SE-90187 Umeå, Sweden.
bioRxiv. 2024 Jan 3:2024.01.02.573960. doi: 10.1101/2024.01.02.573960.
We have developed GmPcides from a peptidomimetic dihydrothiazolo ring-fused 2-pyridone scaffold that have 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 . Screening our compound library for minimal inhibitory (MIC) and minimal bactericidal (MBC) concentrations identified GmPcide PS757 as highly active against . Treatment of 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 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 infections.
我们从一种与二氢噻唑环稠合的肽模拟2-吡啶酮支架开发出了GmPcides，其对多种革兰氏阳性病原体具有抗菌活性。在此，我们通过皮肤和软组织感染（SSTI）及生物膜形成模型研究了GmPcides的治疗效果。通过筛选我们的化合物库以确定最小抑菌（MIC）和最小杀菌（MBC）浓度，发现GmPcide PS757对……具有高活性。用PS757处理生物膜显示出对生物膜形成的所有阶段都有强大的疗效，通过防止初始生物膜形成、停止生物膜成熟和根除成熟生物膜来实现。在SSTI的小鼠模型中，皮下注射PS757导致组织损伤水平降低、细菌载量减少以及伤口愈合速度加快，这与关键毒力因子（包括M蛋白和SpeB半胱氨酸蛋白酶）的下调有关。这些数据表明，GmPcides在治疗……感染方面显示出相当大的前景。
