From antihistamine to anti-infective: Loratadine inhibits regulatory PASTA kinases in Staphylococci to reduce biofilm formation and potentiate β-lactam antibiotics and vancomycin in resistant strains of S. aureus.

Abstract

Staphylococcus epidermidis and Staphylococcus aureus are important human pathogens responsible for two-thirds of all post-surgical infections of indwelling medical devices. Staphylococci form robust biofilms that provide a reservoir for chronic infection and antibiotic resistant isolates are increasingly common in both healthcare and community settings. Novel treatments that can simultaneously inhibit biofilm formation and antibiotic resistance pathways are urgently needed to combat the increasing rates of antibiotic resistant infections. Herein we report that loratadine, an FDA-approved antihistamine, potently inhibits biofilm formation in both S. aureus and S. epidermidis. Furthermore, loratadine potentiates β-lactam antibiotics in methicillin-resistant strains of S. aureus and potentiates both β-lactam antibiotics and vancomycin in vancomycin-resistant strains of S. aureus. Additionally, we elucidate loratadine s mechanism of action as a novel inhibitor of regulatory PASTA kinases in staphylococci and describe how their inhibition affects the expression of genes involved in both biofilm formation and antibiotic resistance in S. epidermidis and S. aureus.