From Antihistamine to Anti-infective: Loratadine Inhibition of Regulatory PASTA Kinases in Staphylococci Reduces Biofilm Formation and Potentiates β-Lactam Antibiotics and Vancomycin in Resistant Strains of <i>Staphylococcus aureus</i>

Abstract

<i>Staphylococcus epidermidis</i> and <i>Staphylococcus aureus</i> are important human pathogens responsible for two-thirds of all postsurgical 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, significantly inhibits biofilm formation in both <i>S. aureus</i> and <i>S. epidermidis</i>. Furthermore, loratadine potentiates β-lactam antibiotics in methicillin-resistant strains of <i>S. aureus</i> and potentiates both β-lactam antibiotics and vancomycin in vancomycin-resistant strains of <i>S. aureus</i>. Additionally, we elucidate loratadine's mechanism of action as a novel inhibitor of the regulatory PASTA kinases Stk and Stk1 in <i>S. epidermidis</i> and <i>S. aureus</i>, respectively. Finally, we describe how Stk1 inhibition affects the expression of genes involved in both biofilm formation and antibiotic resistance in <i>S. epidermidis</i> and <i>S. aureus</i>.