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Proteomic differences between methicillin resistant Staphylococcus aureus showing synergistic effects with cannabinoids

ABSTRACT: Methicillin-resistant Staphylococcus aureus (MRSA) is a major human pathogen in both community and health care settings, which causes a wide range of infections. Its resistance to β-lactam antibiotics and methicillin in particular, greatly complicates treatment options and success rate due to the limited number of antibiotics with activity against MRSA. To further the development of alternative therapeutics, the mechanisms that mediate antibiotic resistance in MRSA need to be fully understood. Cannabinoid compounds including cannabidiol (CBD), tetrahydrocannabinol (THC) and cannabinol (CBN) have shown promise as potential antibiotic adjuvants. In the present study, MRSA cells were subjected to antibiotic stress from methicillin in combination with three cannabinoid compounds, and subsequently analysed using metaproteomics to assess the metabolic response. Subjecting MRSA to methicillin made the cells more viable and increased their energy production, as well as upregulation of penicillin-binding protein 2 (PBP2). The cannabinoids all showed antimicrobial activity against MRSA, and inhibited the energy production of the cells as well as PBP2 when used in combination with methicillin. Furthermore, all three cannabinoid compounds inhibited resistance mechanisms in MRSA, resulting in a decrease in the minimum inhibitory concentration (MIC) of methicillin when used in combination.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Staphylococcus Aureus

SUBMITTER: Jan Struckmann Poulsen

LAB HEAD: Jeppe Lund Nielsen

PROVIDER: PXD024244 | Pride | 2022-01-18

REPOSITORIES: Pride

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Project description: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 a β-lactam antibiotic (oxacillin) and the adjuvant (compound 8). Furthermore, bioinformatic analyses would reveal biochemical pathways enriched in differentially expressed genes. RNA-seq analysis showed 176 and 233 genes significantly up and downregulated, respectively, upon cotreatment with oxacillin and compound 8. We identified four subclusters of genes that were regulated in similar patterns in response to drug treatment. Many of these genes displayed a similar pattern of expression where they were unaffected by compound 8 treatment alone, upregulated upon antibiotic challenge, and downregulated again upon cotreatment. GO categories that were significantly enriched among downregulated genes involved carbohydrate utilization and/or transport. Most of the biochemical pathways enriched with significantly downregulated genes involved carbohydrate utilization, such as the citric acid cycle (p=6.4x10-6) and the phosphotransferase system (p=1.8x10-5). The most populated pathway was S. aureus infection (p=3.0x10-3). Creating a network of affected gene products helped uncover potential master regulators for further investigation. This study revealed a dramatic impact of our lead adjuvant on the transcriptome that is consistent with a pleiotropic effect. These results point to this adjuvant as having potential broad therapeutic use in combatting MRSA infections.

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Proteomic differences between methicillin resistant Staphylococcus aureus showing synergistic effects with cannabinoids

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