Thioridazine affects transcription of genes involved in cell wall biosynthesis in methicillin-resistant Staphylococcus aureus

被引:27
作者
Bonde, Mette [1 ]
Hojland, Dorte H. [1 ]
Kolmos, Hans Jorn [2 ]
Kallipolitis, Birgitte H. [1 ]
Klitgaard, Janne K. [1 ,2 ]
机构
[1] Univ So Denmark, Dept Biochem & Mol Biol, DK-5230 Odense M, Denmark
[2] Univ So Denmark, Res Unit Clin Microbiol, Inst Clin Res, DK-5230 Odense M, Denmark
关键词
MRSA; thioridazine; cell wall biosynthesis; PBP; VraSR; BETA-LACTAM RESISTANCE; VIRULENCE FACTORS; AGR; PHENOTHIAZINES; ANTIBIOTICS; RNAIII; PBP4; TRANSLATION; REGULATORS; OXACILLIN;
D O I
10.1111/j.1574-6968.2011.02255.x
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
The antipsychotic drug thioridazine is a candidate drug for an alternative treatment of infections caused by methicillin-resistant Staphylococcus aureus (MRSA) in combination with the beta-lactam antibiotic oxacillin. The drug has been shown to have the capability to resensitize MRSA to oxacillin. We have previously shown that the expression of some resistance genes is abolished after treatment with thioridazine and oxacillin. To further understand the mechanism underlying the reversal of resistance, we tested the expression of genes involved in antibiotic resistance and cell wall biosynthesis in response to thioridazine in combination with oxacillin. We observed that the oxacillin-induced expression of genes belonging to the VraSR regulon is reduced by the addition of thioridazine. The exclusion of such key factors involved in cell wall biosynthesis will most likely lead to a weakened cell wall and affect the ability of the bacteria to sustain oxacillin treatment. Furthermore, we found that thioridazine itself reduces the expression level of selected virulence genes and that selected toxin genes are not induced by thioridazine. In the present study, we find indications that the mechanism underlying reversal of resistance by thioridazine relies on decreased expression of specific genes involved in cell wall biosynthesis.
引用
收藏
页码:168 / 176
页数:9
相关论文
共 46 条
[1]  
Amaral Leonard, 2004, In Vivo (Attiki), V18, P725
[2]   Insertion of Epicatechin Gallate into the Cytoplasmic Membrane of Methicillin-resistant Staphylococcus aureus Disrupts Penicillin-binding Protein (PBP) 2a-mediated β-Lactam Resistance by Delocalizing PBP2 [J].
Bernal, Patricia ;
Lemaire, Sandrine ;
Pinho, Mariana G. ;
Mobashery, Shahriar ;
Hinds, Jason ;
Taylor, Peter W. .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2010, 285 (31) :24055-24065
[3]   The nature of Staphylococcus aureus MurA and MurZ and approaches for detection of peptidoglycan biosynthesis inhibitors [J].
Blake, Katy L. ;
O'Neill, Alex J. ;
Mengin-Lecreulx, Dominique ;
Henderson, Peter J. F. ;
Bostock, Julieanne M. ;
Dunsmore, Colin J. ;
Simmons, Katie J. ;
Fishwick, Colin W. G. ;
Leeds, Jennifer A. ;
Chopra, Ian .
MOLECULAR MICROBIOLOGY, 2009, 72 (02) :335-343
[4]  
BOURLIOUX P, 1992, APMIS, V100, P40
[5]   Efflux-mediated response of Staphylococcus aureus exposed to ethidium bromide [J].
Couto, Isabel ;
Costa, Sofia Santos ;
Viveiros, Miguel ;
Martins, Marta ;
Amaral, Leonard .
JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY, 2008, 62 (03) :504-513
[6]   Transcription analysis of the Staphylococcus aureus gene encoding penicillin-binding protein 4 [J].
Domanski, TL ;
deJonge, BLM ;
Bayles, KW .
JOURNAL OF BACTERIOLOGY, 1997, 179 (08) :2651-2657
[7]   A Mycobacterium tuberculosis Sigma Factor Network Responds to Cell-Envelope Damage by the Promising Anti-Mycobacterial Thioridazine [J].
Dutta, Noton K. ;
Mehra, Smriti ;
Kaushal, Deepak .
PLOS ONE, 2010, 5 (04)
[8]   Diversity of penicillin-binding proteins -: Resistance factor FmtA of Staphylococcus aureus [J].
Fan, Xin ;
Liu, Yuhong ;
Smith, Daryl ;
Konermann, Lars ;
Siu, K. W. Michael ;
Golemi-Kotra, Dasantila .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2007, 282 (48) :35143-35152
[9]   Antibiotics for Emerging Pathogens [J].
Fischbach, Michael A. ;
Walsh, Christopher T. .
SCIENCE, 2009, 325 (5944) :1089-1093
[10]   Opposing roles of the Staphylococcus aureus virulence regulators, Agr and Sar, in Triton X-100- and penicillin-induced autolysis [J].
Fujimoto, DF ;
Bayles, KW .
JOURNAL OF BACTERIOLOGY, 1998, 180 (14) :3724-3726