Methicillin-resistant Staphylococcus aureus (MRSA) is a major threat to human health, as the US mortality rate outweighs those from HIV, tuberculosis, and viral hepatitis combined. In the wake of the COVID-19 pandemic, antibiotic resistant bacterial infections acquired during hospital stays have increased. Instead of designing and deploying new antibiotics which MRSA would quickly develop resistance to, adjuvants are a key strategy to combatting these bacteria. We have evaluated several small molecule adjuvants that have strong potentiation with β-lactam antibiotics and have now investigated at the molecular level how the lead adjuvant exerts its effects. We hypothesized that the expression levels of key resistance genes would decrease once cotreated with the antibiotic oxacillin and the adjuvant. Furthermore, bioinformatic analyses would reveal biochemical pathways enriched in differentially expressed genes. RNA-seq analysis showed hundreds of genes downregulated upon cotreatment with oxacillin and our lead adjuvant. Many of these genes belonged to the mec and bla operon. As expected, they were upregulated upon antibiotic challenge, and downregulated again upon cotreatment. Multiple hemolysin genes were also significantly downregulated. One of the biochemical pathways most populated with significantly downregulated genes was the S. aureus infection pathway (p=0.003). Mapping genes to this pathway revealed a dramatic impact of our lead adjuvant that is consistent with a pleiotropic effect. These results point to this adjuvant as having potential broad therapeutic use in combatting MRSA infections.

Pleiotropic effects of an antibiotic adjuvant on the MRSA transcriptome

ACS Spring 2022

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