The use of antibacterial drug combinations with synergistic effects is increasingly seen as a critical strategy to combat multi-drug resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA). In this work, the proteome responses in MRSA under the stress of a sub-inhibitory dose of a synergistic drug combination of a novel erythromycin derivative, SIPI-8294, and oxacillin, were studied by label-free quantitative proteomics. Several control treatment groups were designed to isolate proteome responses potentially related to the synergy: (1) the non-synergistic drug combination of erythromycin and oxacillin, (2) SIPI-8294 only, (3) oxacillin only and (4) erythromycin only. Results showed that 200 proteins were differentially expressed in SIPI-8294/oxacillin-treated cells. Among these proteins, the level of penicillin binding protein 2a, the protein mainly responsible for oxacillin resistance in MRSA, was four times lower in the SIPI-8294/oxacillin group than in the erythromycin/oxacillin group, suggesting that SIPI-8294 may interfere with this known oxacillin resistance mechanism. Moreover, hierarchical clustering analysis of differentially expressed proteins under different treatments revealed that SIPI-8294/oxacillin elicits very different responses than the individual drugs or the non-synergistic erythromycin/oxacillin combination. Bioinformatic analysis indicated that the synergistic effect can be further traced to a disruption in oxidation-reduction homeostasis and cell wall biosynthesis.
|Original language||English (US)|
|State||Published - 2016|
Bibliographical noteKAUST Repository Item: Exported on 2021-07-07
Acknowledgements: We thank Joyce Wong for technical assistance with the LC-MS/MS, HKUST Biosciences Central Research Facility (BioCRF) for providing mass spectrometry services and Materials Characterization and Preparation Facility (MCPF) for providing scanning electron microscope. We also thank Prof. Shunyi Shen in Shanghai Institute of Pharmaceutical Industry for providing SIPI-8294 for the mechanism study. This research is supported by the Research Grant Council of the Hong Kong Special Administrative Region Government, China (Grant No. 16302614 and 16100415) and the National Natural Science Foundation of China (Grant No. 81273413 and 81573329).
This publication acknowledges KAUST support, but has no KAUST affiliated authors.
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