title: Proteomic response of methicillin-resistant S. aureus to a synergistic antibacterial drug combination: a novel erythromycin derivative and oxacillin.
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.
authors.affiliation: Department of Chemical and Biomolecular Engineering, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong.|Institute of Antibiotics, Huashan Hospital affiliated to Fudan University, Shanghai, China.|Key Laboratory of Clinical Pharmacology of Antibiotics, National Population and Family Planning Commission, Shanghai, China.
authors.forename: Xiaofen
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Chemical and Biomolecular Engineering, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong.|Graduate School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.|Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Pei-Jin
authors.initials: PJ
authors.lastname: Pai
authors.affiliation: KAUST Global Partnership program, Division of Life Science, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong.
authors.forename: Weipeng
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Chemical and Biomolecular Engineering, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong.
authors.forename: Yingwei
authors.initials: Y
authors.lastname: Hu
authors.affiliation: State Key Laboratory of New Drug and Pharmaceutical Process, Shanghai Institute ofPharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai, China.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Dong
authors.affiliation: KAUST Global Partnership program, Division of Life Science, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong.
authors.forename: Pei-yuan
authors.initials: PY
authors.lastname: Qian
authors.affiliation: State Key Laboratory of New Drug and Pharmaceutical Process, Shanghai Institute ofPharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai, China.|School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Daijie
authors.initials: D
authors.lastname: Chen
authors.affiliation: Department of Chemical and Biomolecular Engineering, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong.|Division of Biomedical Engineering, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong.
authors.forename: Henry
authors.initials: H
authors.lastname: Lam
mesh_terms: D018432:Drug Resistance, Multiple / Q000235:genetics; D004357:Drug Synergism; D004917:Erythromycin / Q000031:analogs & derivatives / Q000494:pharmacology*; D006801:Humans; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics / Q000472:pathogenicity; D010068:Oxacillin / Q000494:pharmacology*; D046915:Penicillin-Binding Proteins / Q000235:genetics; D020543:Proteome / Q000187:drug effects / Q000235:genetics; D040901:Proteomics
chemical_list: D046915:Penicillin-Binding Proteins; D020543:Proteome; D004917:Erythromycin; D010068:Oxacillin