Department of Molecular Microbiology, Center for Women's Infectious Disease Research, Washington University School of Medicine, St. Louis, MO 63110, USA.
Department of Chemistry, Umeå University, SE-90187 Umeå, Sweden.
Sci Adv. 2024 Aug 2;10(31):eadn7979. doi: 10.1126/sciadv.adn7979.
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 . 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.
我们从具有抗广谱革兰氏阳性病原体抗菌活性的二氢噻唑并环融合 2-吡啶酮肽模拟物支架中开发了 GmPcides。在这里，我们使用皮肤和软组织感染 (SSTI) 和生物膜形成模型来检查 GmPcides 的治疗效果。通过筛选我们的化合物文库以确定最小抑制浓度 (MIC) 和最小杀菌浓度 (MBC)，发现 GmPcide PS757 对 具有高度活性。用 PS757 处理生物膜可防止初始生物膜形成、阻止生物膜成熟和消除成熟生物膜，从而对生物膜形成的所有阶段均显示出强大的功效。在 的 SSTI 小鼠模型中，PS757 的皮下给药导致组织损伤水平降低、细菌负荷减少和伤口愈合速度加快，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 感染方面具有很大的潜力。
