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RNA-seq-based transcriptome analysis of a cefquinome-treated, highly resistant, and virulent MRSA strain

ABSTRACT: Cefquinome is a fourth-generation cephalosporin developed specifically for veterinary use. The mechanism of MRSA resistance to cefquinome is still not established. Therefore, we designed this study to evaluate the effect of cefquinome on the transcriptome of MRSA1679a, a strain that was isolated from a chicken. The transcriptome analysis indicated that multiple efflux pumps (QacA, NorB, Bcr, and ABCb) were upregulated in MRSA1679a as a resistance mechanism to expel cefquinome. Additionally, penicillin-binding protein 1A was overexpressed, which conferred resistance to cefquinome, a β-lactam antibiotic. Adhesion and the biofilm-forming capacity of the MRSA strain was also enhanced in addition to overexpression of many stress-related genes. Genes related to carbohydrate metabolism, secretion systems, and transport activity were also significantly increased in MRSA1679a. In conclusion, global transcription was triggered to overcome the stress induced by cefquinome, and the MRSA1679a showed a great genetic potential to survive in this challenging environment. This study provides a profound understanding of MRSA1679a as a potentially important pathogen and identifies key resistance characteristics of MRSA against cefquinome.

ORGANISM(S): Staphylococcus aureus

PROVIDER: GSE179977 | GEO | 2021/10/18

REPOSITORIES: GEO

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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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RNA-seq-based transcriptome analysis of a cefquinome-treated, highly resistant, and virulent MRSA strain

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