Mechanism of synergy between SIPI-8294 and β-lactam antibiotics against methicillin-resistant Staphylococcus aureus.

UNLABELLED: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. SIGNIFICANCE AND IMPACT OF THE STUDY: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.