Abstract：
The primary obstacles in the management of Enterococcus and Streptococcal infections are drug resistance and biofilm formation. Our study revealed that loratadine at a concentration of ≥25 μM exhibited significant inhibitory effects on biofilm formation in 167 clinical strains of Enterococcus faecalis and 15 clinical isolates of Streptococcus agalactiae, Streptococcus pyogenes, and Streptococcus pneumoniae. Additionally, the antibiofilm activity against E. faecalis and Streptococcal was demonstrated by several loratadine derivatives with altered side-chain carbamate moieties. This study investigated the antibacterial activity of the loratadine derivative Lo-7 against clinical strains of S. agalactiae and S. pyogenes, with minimum inhibitory concentrations ranging from 12.5 to 25 μM. The findings revealed that a low concentration of loratadine derivative Lo-7 (3.125 μM) significantly augmented the bactericidal efficacy of vancomycin against multidrug-resistant (MDR) S. agalactiae, both in vitro and in vivo. The loratadine derivative Lo-7, even at low concentrations, demonstrated significant efficacy in eliminating intracellular MDR S. agalactiae within macrophages, potentially indicating a unique advantage over vancomycin, linezolid, and loratadine. Mechanistically, exposure to the loratadine derivative Lo-7 resulted in membrane depolarization without affecting membrane permeability in S. agalactiae. The potential targeting of the SecG subunit of the SecYEG membrane-embedded channel by the loratadine derivative Lo-7 in S. agalactiae was identified through quantitative proteomics, a drug affinity responsive target stability assay, and molecular docking.
摘要：
管理肠球菌和链球菌感染的主要障碍是耐药性和生物膜形成。我们的研究表明，浓度≥25μM的氯雷他定对167个粪肠球菌临床菌株和15个无乳链球菌临床分离株的生物膜形成具有显着的抑制作用，化脓性链球菌,和肺炎链球菌。此外,一些侧链氨基甲酸酯部分改变的氯雷他定衍生物证明了抗粪肠球菌和链球菌的抗生物膜活性.这项研究调查了氯雷他定衍生物Lo-7对无乳链球菌和化脓性链球菌临床菌株的抗菌活性，最小抑制浓度为12.5至25μM。研究结果表明，低浓度的氯雷他定衍生物Lo-7（3.125μM）显着增强了万古霉素对多药耐药（MDR）无乳链球菌的杀菌功效，在体外和体内。氯雷他定衍生物Lo-7，即使在低浓度下，在消除巨噬细胞内的细胞内MDR无乳链球菌方面表现出显著功效，可能表明与万古霉素相比具有独特的优势，利奈唑胺,还有氯雷他定.机械上,暴露于氯雷他定衍生物Lo-7导致膜去极化而不影响无乳链球菌的膜通透性。通过定量蛋白质组学鉴定了无乳链球菌氯雷他定衍生物Lo-7对SecYEG膜包埋通道的SecG亚基的潜在靶向，药物亲和力响应靶标稳定性测定，和分子对接。
