Abstract
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.
Highlights
The past few decades[7]
Sub-minimum inhibitory concentration (MIC) doses of antibiotics and SIPI-8294 were applied to Methicillin-resistant S. aureus (MRSA), so as to impose stress to the cells but not induce non-specific effects associated with cell death
In order to understand the synergistic mechanism of SIPI-8294 and oxacillin, spectral counting based label-free quantitative proteomics was applied
Summary
The past few decades[7]. several newer antibiotics introduced after 2000, such as linezolid and daptomycin, remain largely effective against MRSA, strains resistant to those antibiotics have already been reported[8,9]. Elucidation of the mechanism underlying such effects has been difficult, partly because traditional reductionist approaches mainly focused on the immediate drug targets and the addition or modification of individual cellular components that underlie the resistance[11,12]. This is unlikely to reveal the long chain of interactions that are likely to be responsible for synergistic effects caused by multiple drugs. This study aimed at revealing the global cellular responses of MRSA against sub-MIC dose of SIPI-8294 and oxacillin, and thereby obtaining new insights into the synergistic mechanism of the drug combination
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