Beattie Sarah R, Esan Taiwo, Zarnowski Robert, Eix Emily, Nett Jeniel E, Andes David R, Hagen Timothy, Krysan Damian J
Department of Pediatrics, Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City IA.
Department of Chemistry and Biochemistry, Northern Illinois University, 1425 West Lincoln Highway, DeKalb IL.
bioRxiv. 2023 Jan 20:2023.01.19.524835. doi: 10.1101/2023.01.19.524835.
New antifungal therapies are needed for both systemic, invasive infections as well as superficial infections of mucosal and skin surfaces as well as biofilms associated with medical devices. The resistance of biofilm and biofilm-like growth phases of fungi contributes to the poor efficacy of systemic therapies to non-systemic infections. Here, we describe the identification and characterization of a novel keto-alkyl-pyridinium scaffold with broad spectrum activity (2-16 µg/mL) against medically important yeasts and moulds, including clinical isolates resistant to azoles and/or echinocandins. Furthermore, these keto-alkyl-pyridinium agents retain substantial activity against biofilm phase yeast and have direct activity against hyphal . Although their toxicity precludes use in systemic infections, we found that the keto-alkyl-pyridinium molecules reduce fungal burden in a rat model of vascular catheter infection and reduce colonization in a porcine ex vivo model. These initial pre-clinical data suggest that molecules of this class may warrant further study and development.
对于全身性侵袭性感染以及粘膜和皮肤表面的浅表感染以及与医疗器械相关的生物膜，都需要新的抗真菌疗法。真菌生物膜和生物膜样生长阶段的耐药性导致全身疗法对非全身性感染的疗效不佳。在此，我们描述了一种新型酮烷基吡啶鎓支架的鉴定和表征，该支架对医学上重要的酵母和霉菌具有广谱活性（2-16μg/mL），包括对唑类和/或棘白菌素耐药的临床分离株。此外，这些酮烷基吡啶鎓剂对生物膜阶段的酵母保持显著活性，并对菌丝具有直接活性。尽管它们的毒性使其无法用于全身性感染，但我们发现酮烷基吡啶鎓分子在血管导管感染大鼠模型中可减轻真菌负荷，并在猪离体模型中减少定植。这些初步的临床前数据表明，这类分子可能值得进一步研究和开发。
