Many infections that appear in both healthcare and community environments are due to Methicillin-resistant Staphylococcus aureus (MRSA) which has become challenging to treat as the bacteria quickly form resistance against new antibiotics. Instead of synthesizing and deploying new antibiotics which would be a long and costly process, antibiotic adjuvants can be utilized. These adjuvants minimize resistance mechanisms of MRSA, which allow for the antibiotics to potentiate their effects. We have evaluated several small molecule adjuvants that are effective in potentiating β-lactam antibiotics and are continuing to look at the effects on a molecular level. Previously, we have focused on several key resistance genes, but now we hypothesize that there are many more genes that change transcriptome-wide as a result of adjuvant cotreatment. We treated cultures of MRSA with oxacillin and/or our lead adjuvant and purified total RNA. The RNA-seq data revealed-hundreds of genes that showed differential expression upon co-treatment of oxacillin and our adjuvant. To validate this high through put data, we analyzed a subset of genes via RT-qPCR on independent samples to compare the results. We found the data to be consistent with previous data we had for genes in the mec and bla operons, which were down regulated upon cotreatment. Other genes which we noticed had large differential expression included upregulation of hrt A and B, genes critical for heme homeostasis. Additionally, hlg A and B (gamma-hemolysins), underwent down regulation upon cotreatment. With our RT-qPCR experiments, we validated these RNA-seq results at a rate of 71%. Another significant result of our RNA-seq data was the enrichment of genes within the S. aureous infection pathway (p=0.003). Together, these results are consistent with pleiotropic effect of this antibiotic adjuvant.

Pleitropic effects of small molecule antibiotic adjuvants on the MRSA transcriptome

ACS Spring 2022

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