Loratadine decreases virulence of methicillin-resistant Staphylococcus aureus by widespread disruption of hemolysis in both Stk1-dependent and –independent fashions
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Methicillin-resistant Staphylococcus aureus (MRSA) is a bacterial pathogen that relies on expression of a wide range of virulence factors. Hemolysins are a diverse collection of cytolytic toxins that promote virulence by being excreted and lysing host blood cells. We previously reported on novel anti-virulence compounds that modulate hemolysis in vitro, including a brominated carbazole (compound 8) and the active ingredient in Claritin (loratadine). We analyzed expression and activity of MRSA hemolysins in two hospital-acquired strains. Even with the same staphylococcal cassette chromosome mec (SCC mec ) type, the strains displayed unique responses to loratadine where both repression and elevation of hemolysis occurred. We hypothesized that modulation of hemolysis by these putative Stk1 inhibitors would extend to community-acquired strains of MRSA. Furthermore, we wanted to determine if Stk1 was the only hemolysis regulatory protein being engaged by these compounds. To test this, we examined compound 8 and loratadine’s effects on two different USA300 strains, in addition to deletion mutants for a range of hemolysis regulatory genes. We observed strain-specific regulation of hemolysis by Stk1. Loratadine continued to downregulate both alpha and beta hemolytic activity in USA300 JE2 in both Stk1-dependent and independent pathways. Finally, we report that this anti-virulence compound effectively disrupts hemolysis by modulating global regulators at the mRNA level including the agr and vraRS systems that likely contribute to reduced hemolysin levels. Both hla and hld mRNA reductions extended to a human cell line model of MRSA infection. Together, these results expand our knowledge of loratadine’s function as a virulence modulator.
Importance
Methicillin-resistant Staphylococcus aureus (MRSA) is a human pathogen of concern worldwide. It can cause infections of the skin, soft tissue, blood, and lungs, among others, in both community and hospital settings. This work evaluates loratadine, the active ingredient in Claritin, as an anti-virulence compound. We show that loratadine is effective at lowering expression of hemolysin genes in MRSA and, concomitantly, lessening host blood cell hemolysis due to staphylococcal hemolysin proteins. This effect occurs in the presence and absence of loratadine’ proposed target, a serine-threonine kinase called Stk1. In a model of human infection, every hemolysin gene expression is also downregulated by loratadine. This FDA-approved antihistamine has many properties that warrant repurposing as an anti-virulence therapy.
