Loratadine Combats Methicillin-Resistant Staphylococcus aureus by Modulating Virulence, Antibiotic Resistance, and Biofilm Genes

Methicillin-resistant Staphylococcus aureus (MRSA) has evolved to become
resistant to multiple classes of antibiotics.
New antibiotics are costly to develop and deploy, and they have a
limited effective lifespan. Antibiotic adjuvants are molecules that
potentiate existing antibiotics through nontoxic mechanisms. We previously
reported that loratadine, the active ingredient in Claritin, potentiates
multiple cell-wall active antibiotics in vitro and
disrupts biofilm formation through a hypothesized inhibition of the
master regulatory kinase Stk1. Loratadine and oxacillin combined repressed
the expression of key antibiotic resistance genes in the bla and mec operons. We hypothesized that additional
genes involved in antibiotic resistance, biofilm formation, and other
cellular pathways would be modulated when looking transcriptome-wide.
To test this, we used RNA-seq to quantify transcript levels and found
significant effects in gene expression, including genes controlling
virulence, antibiotic resistance, metabolism, transcription (core
RNA polymerase subunits and sigma factors), and translation (a plethora
of genes encoding ribosomal proteins and elongation factor Tu). We
further demonstrated the impacts of these transcriptional effects
by investigating loratadine treatment on intracellular ATP levels,
persister formation, and biofilm formation and morphology. Loratadine
minimized biofilm formation in vitro and enhanced
the survival of infected Caenorhabditis elegans. These pleiotropic effects and their demonstrated outcomes on MRSA
virulence and survival phenotypes position loratadine as an attractive
anti-infective against MRSA.