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.