Restoration of antibiotic susceptibility in methicillin-resistant Staphylococcus aureus by targeting mecR1 with a phosphorothioate deoxyribozyme.
1. Methicillin resistance in Staphylococcus aureus is mediated by the mecA gene. The mecA gene encodes a penicillin-binding protein (PBP2a) possessing low beta-lactam affinity. Transcription of mecA is regulated by a signal transduction system consisting of the sensor/transducer MecR1. Disruption of the MecR1 regulatory pathway may inhibit mecA expression and restore methicillin-resistant Staphylococcus aureus (MRSA) susceptibility to beta-lactams. 2. In the present study, a phosphorothioate deoxyribozyme (named PS-DRz147) specifically targeting MecR1 mRNA was designed, synthesised and introduced into the MRSA strain WHO-2. 3. The expression of mecR1 and mecA was inhibited by PS-DRz147 in a concentration-dependent manner. Consequently, the susceptibility of WHO-2 colonies to the antibiotic oxacillin was restored. 4. The results of the present study indicate that blockade of the MecR1-MecI-MecA signalling pathway with an mecR1-targeted DNAzyme can restore the susceptibility of MRSA to existing beta-lactam antibiotics.
Hou
Zheng
Z
Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, China.
Meng
Jing-Ru
JR
Niu
Chao
C
Wang
Hai-Fang
HF
Liu
Jie
J
Hu
Ben-Quan
BQ
Jia
Min
M
Luo
Xiao-Xing
XX
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D015169:Colony Count, Microbial; D021881:DNA, Catalytic / Q000378:metabolism*; D015964:Gene Expression Regulation, Bacterial; D016106:Methicillin Resistance / Q000235:genetics; D008826:Microbial Sensitivity Tests; D010068:Oxacillin / Q000494:pharmacology*; D046915:Penicillin-Binding Proteins; D012329:RNA, Bacterial / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D013873:Thionucleotides / Q000378:metabolism*
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D021881:DNA, Catalytic; C101640:MecI protein, Staphylococcus; D046915:Penicillin-Binding Proteins; D012329:RNA, Bacterial; D012333:RNA, Messenger; D012097:Repressor Proteins; D013873:Thionucleotides; C487789:mecA protein, Staphylococcus aureus; C101641:mecR1 protein, Staphylococcus aureus; D010068:Oxacillin