Dataset Information

Label-free quantitative proteomics reveals synergistic mechanism of a new erythromycin derivative and oxacillin against methcillin-resistant S. aureus

ABSTRACT: Methicillin-resistant Staphylococcus aureus (MRSA) remains a global health threat with an over 14% fatality rate, in case of invasive infection, in 2011. Multi-drug resistance is the main reason for the failure of therapy. Use of antimicrobial drug combinations with synergistic effect is increasingly seen as a critical strategy to combat multi-drug resistant pathogens such as MRSA. However, the mechanism of synergistic effect has yet been systematically studied. In this work, we investigated a new erythromycin derivative, SIPI-8294, which has been demonstrated to have synergistic effect with oxacillin against MRSA, unlike its parent compound erythromycin. To obtain insights into the mechanism for the synergistic effect, label-free quantitative proteomics was employed. Cultured MRSA was exposed to sub-inhibitory doses of oxacillin, SIPI-8294, erythromycin, and combinations of SIPI-8294/oxacillin and erythromycin/oxacillin to reveal the global proteome responses to drug treatment. Results showed that 200 proteins were differentially expressed in SIPI-8294/oxacillin-treated cells. Among these proteins, the expression levels of penicillin binding protein 2a and β-lactamase, two proteins mainly responsible for oxacillin resistance, were four times lower in the SIPI-8294/oxacillin treatment group than in the erythromycin/oxacillin treatment group. Quantitative real-time PCR analysis also revealed similar trends at the transcription level. These results suggest that the synergistic mechanism may be related to interference with the known oxacillin resistance mechanism. The data also provided some evidence that the combination of SIPI-8294 and oxacillin appears to impact oxidation-reduction homeostasis and cell wall biosynthesis.

INSTRUMENT(S): LTQ

ORGANISM(S): Staphylococcus Aureus

SUBMITTER: Liu Xiaofen

LAB HEAD: Henry Lam

PROVIDER: PXD001494 | Pride | 2022-03-01

REPOSITORIES: Pride

ACCESS DATA

Similar Datasets

Project description:Several groups have shown that through evolution experiments, tolerance evolved rapidly under cyclic antibiotic treatment which then promote the emergence of resistance. In other words, intermittent antibiotic exposure will “train” the bacteria to become tolerant to the drug, and then boost the chances for them to become fully resistant. This evolutionary trajectory of evolving tolerance and resistance not only occurs in vitro, but also in clinical patients with MRSA blood infections. Despite the fact that repetitive antibiotic treatment will lead to tolerance and resistance development in bacterial populations, the difference on the evolutionary path between those treated with a single drug and drug combination remains unaddressed. In this study, we monitored the development of tolerance in MRSA by treating them with either daptomycin alone for 2 weeks (Scheme 1), or daptomycin combined with rifampin for two weeks (Scheme 2), in a cyclic manner. In addition, we also investigate another scenario where we treat MRSA cells with daptomycin alone for one week, and subsequently treat them with daptomycin and rifampin combination in the second week (Scheme 3). At the end of the evolution experiment, we observed that the population from Scheme 1 developed tolerance towards daptomycin, the population from Scheme 2 developed both tolerance and resistance towards daptomycin, while the population from Scheme 3 developed tolerance after a week of treatment, but then the tolerance phenotype diminished at the end of the second week due to the drug combination treatment. We subjected them to whole genome sequencing and identified single point mutations that are responsible for the observed phenotype. Through proteomics, we compared the proteome profile of the population evolved from scheme 1 (S1D14), scheme 2 (S2D14) and scheme 3 (S3D14), and we observed that these three populations employ distinct mechanisms to survive antibiotic treatment, suggesting that the treatment strategy for these populations should be tailored depending on the treatment conditions.

Dataset Information

Label-free quantitative proteomics reveals synergistic mechanism of a new erythromycin derivative and oxacillin against methcillin-resistant S. aureus

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure