Rampacci Elisa, Felicetti Tommaso, Cernicchi Giada, Stefanetti Valentina, Sabatini Stefano, Passamonti Fabrizio
Department of Veterinary Medicine, University of Perugia, Via San Costanzo 4, 06126 Perugia, Italy.
Department of Pharmaceutical Sciences, Via Del Liceo 1, 06123 Perugia, Italy.
Antibiotics (Basel). 2023 Apr 24;12(5):806. doi: 10.3390/antibiotics12050806.
One promising approach in treating antibiotic-resistant bacteria is to "break" resistances connected with antibacterial efflux by co-administering efflux pump inhibitors (EPIs) with antibiotics. Here, ten compounds, previously optimized to restore the susceptibility to ciprofloxacin (CIP) of -overexpressing , were evaluated for their ability to inhibit -mediated efflux in and synergize with CIP, ethidium bromide (EtBr), gentamycin (GEN), and chlorhexidine digluconate (CHX). We focused efforts on as a pathogenic bacterium of concern within veterinary and human medicine. By combining data from checkerboard assays and EtBr efflux inhibition experiments, the hits 2-arylquinoline , dihydropyridine and 2-phenyl-4-carboxy-quinoline were considered the best EPIs for . Overall, most of the compounds, except for 2-arylquinoline compound , were able to fully restore the susceptibility of to CIP and synergize with GEN as well, while the synergistic effect with CHX was less significant and often did not show a dose-dependent effect. These are valuable data for medicinal chemistry optimization of EPIs for and lay the foundation for further studies on successful EPIs to treat staphylococcal infections.
治疗耐抗生素细菌的一种有前景的方法是通过将外排泵抑制剂（EPI）与抗生素联合使用来“打破”与抗菌外排相关的耐药性。在此，对十种先前经过优化以恢复过表达菌株对环丙沙星（CIP）敏感性的化合物，评估了它们在菌株中抑制介导的外排以及与CIP、溴化乙锭（EtBr）、庆大霉素（GEN）和葡萄糖酸洗必泰（CHX）协同作用的能力。我们将重点放在作为兽医和人类医学中关注的病原菌的菌株上。通过结合棋盘法测定和EtBr外排抑制实验的数据，命中的2-芳基喹啉、二氢吡啶和2-苯基-4-羧基喹啉被认为是针对菌株的最佳EPI。总体而言，除2-芳基喹啉化合物外，大多数化合物能够完全恢复菌株对CIP的敏感性并与GEN协同作用，而与CHX的协同作用不太显著且通常不显示剂量依赖性效应。这些是用于菌株EPI药物化学优化的有价值数据，并为进一步研究成功治疗葡萄球菌感染的EPI奠定了基础。
