He M, Shao L, Liu Q, Li J, Lin H, Jing L, Li M, Chen D
Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai, China.
Department of Laboratory Medicine, School of Medicine, Renji Hospital, Shanghai Jiaotong University, Shanghai, China.
Lett Appl Microbiol. 2016 Jul;63(1):3-10. doi: 10.1111/lam.12583. Epub 2016 Jun 3.
SIPI-8294, as an erythromycin derivative, has only weak antibacterial effects on MRSA and MSSA. Interestingly, synergistic effect of SIPI-8294 with oxacillin was observed both in vitro and in vivo. Western blot and RT-PCR results demonstrate that mecA expressions were suppressed by SIPI-8294 in MRSA. Furthermore, the knock out of mecA in ATCC 43300 led to the loss of synergy of the combinations while mecA complemented strain showed almost the same synergistic capability compared to the wild type strain. However, the knock out of mecR1 and mecI in MRSA displayed no impact on the synergy of the combinations and the ability of SIPI-8294 to suppress mecA expression. In summary, our study has demonstrated that SIPI-8294 could dramatically reverse MRSA resistance to β-lactams both in vitro and in vivo owing to inhibiting mecA expression. However, mecR1 and mecI, as the pivotal regulatory genes of mecA, do not participate in SIPI-8294-mecA pathway. The research indicates that it may be a promising strategy for combating MRSA infections with the combinations of SIPI-8294 and β-lactam antibiotics. The research of the mechanism is important for structure modification and new drug development.
This study is the first report on the mechanism of synergy between SIPI-8294 and β-lactams against MRSA on the molecular level. In this study, SIPI-8294 showed strong synergistic effects on β-lactam antibiotics both in vitro and in vivo owing to inhibiting mecA expression. As pivotal regulatory genes of mecA, mecR1 and mecI do not participate in SIPI-8294-mecA pathway and are not involved in the synergism of SIPI-8294 and β-lactams. The research indicates that it may be a promising strategy for combating MRSA infections with the combinations of SIPI-8294 and β-lactams. The research is important for structure modification and new drug development.
SIPI-8294作为一种红霉素衍生物，对耐甲氧西林金黄色葡萄球菌（MRSA）和甲氧西林敏感金黄色葡萄球菌（MSSA）仅具有微弱的抗菌作用。有趣的是，在体外和体内均观察到SIPI-8294与苯唑西林具有协同作用。蛋白质免疫印迹法（Western blot）和逆转录-聚合酶链反应（RT-PCR）结果表明，SIPI-8294可抑制MRSA中mecA的表达。此外，敲除ATCC 43300中的mecA会导致联合用药失去协同作用，而mecA互补菌株与野生型菌株相比显示出几乎相同的协同能力。然而，敲除MRSA中的mecR1和mecI对联合用药的协同作用以及SIPI-8294抑制mecA表达的能力没有影响。总之，我们的研究表明，由于抑制mecA表达，SIPI-8294在体外和体内均可显著逆转MRSA对β-内酰胺类抗生素的耐药性。然而，mecR1和mecI作为mecA的关键调控基因，不参与SIPI-8294-mecA途径。该研究表明，SIPI-8294与β-内酰胺类抗生素联合使用可能是对抗MRSA感染的一种有前景的策略。该作用机制的研究对于结构修饰和新药开发具有重要意义。
本研究是关于SIPI-8294与β-内酰胺类抗生素对MRSA协同作用机制的首次分子水平报道。在本研究中，由于抑制mecA表达，SIPI-8294在体外和体内对β-内酰胺类抗生素均显示出强大的协同作用。作为mecA的关键调控基因，mecR1和mecI不参与SIPI-8294-mecA途径，也不参与SIPI-8294与β-内酰胺类抗生素的协同作用。该研究表明，SIPI-8294与β-内酰胺类抗生素联合使用可能是对抗MRSA感染的一种有前景的策略。该研究对于结构修饰和新药开发具有重要意义。
