| Autor: |
Viering BL; Department of Chemistry, High Point University, High Point, North Carolina 27268, United States., Balogh H; Department of Chemistry, High Point University, High Point, North Carolina 27268, United States., Cox CF; Department of Chemistry, High Point University, High Point, North Carolina 27268, United States., Kirpekar OK; Department of Chemistry, High Point University, High Point, North Carolina 27268, United States., Akers AL; Department of Chemistry, High Point University, High Point, North Carolina 27268, United States., Federico VA; Department of Biology, High Point University, High Point, North Carolina 27268, United States., Valenzano GZ; Department of Chemistry, High Point University, High Point, North Carolina 27268, United States., Stempel R; Department of Chemistry, High Point University, High Point, North Carolina 27268, United States., Pickett HL; Department of Biology, High Point University, High Point, North Carolina 27268, United States., Lundin PM; Department of Chemistry, High Point University, High Point, North Carolina 27268, United States., Blackledge MS; Department of Chemistry, High Point University, High Point, North Carolina 27268, United States., Miller HB; Department of Chemistry, High Point University, High Point, North Carolina 27268, United States. |
| Abstrakt: |
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. |
