Identification of natural molecules as antimicrobials or β-lactam resistance modifying agents against Staphylococcus aureus

Staphylococcus aureus is a major cause of community- and hospital- acquired infections, with β-lactams often considered as the first line of treatment. However, since their emergence, methicillin-resistant S. aureus (MRSA) strains have evolved resistance to multiple classes of antibiotics, making the discovery of novel antimicrobials or treatment regimens urgently needed. Given the potential of natural molecules, we screened 12 plants used in traditional medicine in Africa for their direct (used alone) or indirect (combined with β-lactams) antistaphylococcal activities. Focusing on the most promising extract, the leaf dichloromethane extract from the shea butter tree (Vitellaria paradoxa), we identified 5 triterpenic acids together with 6 triterpenic esters. After having associated the antimicrobial activity of this crude extract to its high contents in ursolic (21%) and oleanolic (6%) acids, we showed that both compounds synergized with two β-lactams (ampicillin & oxacillin). Exploring their mechanism of action, we showed that both compounds caused a delocalization of PBP2 from the cell wall biosynthetic machinery site as well as an inhibition of β-lactamases in living bacteria. Moreover, we showed that local administration of UA provided a synergistic benefit to nafcillin in reducing lesion size and inflammatory cytokine production in a murine model of subcutaneous MRSA infection. Finally, all isolated/identified compounds were tested in vitro for their antiparasitic activity as well as for their cytotoxicity. One isolated triterpenic ester showed a promising antitrypanosomal activity (IC50 = 0.79 µg/mL) with a low cytotoxicity (IC50 = 21.04 µg/mL) and was shown to decrease the parasitemia and to improve significantly the survival of Trypanosoma brucei brucei infected mice. This work thus showed that the underexplored leaves of the well-known shea butter tree contain interesting compounds to fight against MRSA as well as Trypanosoma.