Loratadine Derivative Lo-7: A Weapon against Drug-Resistant Enterococcus and Streptococcal Infections.

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.