Sepsis induced by methicillin-resistant Staphylococcus aureus (MRSA) has worse outcome because of multiresistance to a large group of
antibiotics, which may lead to death from
septic shock. In the present study, we firstly found that
artesunate in combination with
oxacillin was capable of protecting mice challenged with live MRSA WHO-2 (WHO-2) and the protection was related to the reduced TNF-α and
IL-6 levels and decreased bacterial load. Based on above results,
artesunate was further investigated from two aspects in vitro, anti-
inflammation effect and antibacterial enhancement effect on
antibiotics.
Artesunate not only inhibited TNF-α and
IL-6 release but also inhibited
mRNA and
protein expressions of TLR2 and Nod2, two important receptors, in murine peritoneal macrophages stimulated with heat-killed WHO-2, further demonstrating anti-inflammatory effect of
artesunate was related to the inhibition of TLR2- and Nod2-mediated proinflammatory
cytokines. Significantly,
artesunate enhanced antibacterial activity of
oxacillin and
ampicillin not
levofloxacin against WHO-2 and a clinical MRSA strain; the fractional inhibitory concentration indexes were lower than 0.5. Further,
artesunate possessed moderate affinity for
penicillin-binding protein 2a (PBP2a) and reduced the
mecA mRNA expression up-regulated by
oxacillin, suggesting that
artesunate's enhancement on antibacterial activity of β-
lactams was related to the inhibition of PBP2a and down-regulation of
mecA mRNA expression. In conclusion, our results demonstrated that
artesunate in combination with
oxacillin protected mice challenged with lethal live MRSA via its inhibition on proinflammatory
cytokines release and enhancement on antibacterial activity of
oxacillin.
Artesunate could be further investigated as a candidate drug for MRSA
sepsis.