1. Molecules. 2017 Dec 16;22(12). pii: E2245. doi: 10.3390/molecules22122245.

Synergy between Ursolic and Oleanolic Acids from Vitellaria paradoxa Leaf Extract
and β-Lactams against Methicillin-Resistant Staphylococcus aureus: In Vitro and
In Vivo Activity and Underlying Mechanisms.

Catteau L(1)(2), Reichmann NT(3), Olson J(4), Pinho MG(5), Nizet V(6)(7), Van
Bambeke F(8), Quetin-Leclercq J(9)(10).

Author information: 
(1)Pharmacognosy Research Group, Louvain Drug Research Institute, Université
catholique de Louvain, 1200 Brussels, Belgium. lucy.catteau@uclouvain.be.
(2)Cellular and Molecular Pharmacology Research Group, Louvain Drug Research
Institute, Université catholique de Louvain, 1200 Brussels, Belgium.
lucy.catteau@uclouvain.be.
(3)Bacterial Cell Biology Laboratory, Instituto de Tecnologia Química e Biológica
António Xavier, Universidade Nova de Lisboa, 2780-157 Oeiras, Portugal.
nreichmann@itqb.unl.pt.
(4)Department of Pediatrics, University of California, San Diego, La Jolla, CA
92093-0760, USA. jolson@ucsd.edu.
(5)Bacterial Cell Biology Laboratory, Instituto de Tecnologia Química e Biológica
António Xavier, Universidade Nova de Lisboa, 2780-157 Oeiras, Portugal.
mgpinho@itqb.unl.pt.
(6)Department of Pediatrics, University of California, San Diego, La Jolla, CA
92093-0760, USA. vnizet@ucsd.edu.
(7)Skaggs School of Pharmacy and Pharmaceutical Sciences, University of
California, San Diego, La Jolla, CA 92093-0760, USA. vnizet@ucsd.edu.
(8)Cellular and Molecular Pharmacology Research Group, Louvain Drug Research
Institute, Université catholique de Louvain, 1200 Brussels, Belgium.
francoise.vanbambeke@uclouvain.be.
(9)Pharmacognosy Research Group, Louvain Drug Research Institute, Université
catholique de Louvain, 1200 Brussels, Belgium. joelle.leclercq@uclouvain.be.
(10)MASSMET Platform, Louvain Drug Research Institute, Université catholique de
Louvain, 1200 Brussels, Belgium. joelle.leclercq@uclouvain.be.

Combining antibiotics with resistance reversing agents is a key strategy to
overcome bacterial resistance. Upon screening antimicrobial activities of plants 
used in traditional medicine, we found that a leaf dichloromethane extract from
the shea butter tree (Vitellaria paradoxa) had antimicrobial activity against
methicillin-resistant Staphylococcus aureus (MRSA) with further evidence of
synergy when combined with β-lactams. Using HPLC-MS, we identified ursolic (UA)
and oleanolic acids (OA) in leaves and twigs of this species, and quantified them
by HPLC-UV as the major constituents in leaf extracts (21% and 6% respectively). 
Both pure triterpenic acids showed antimicrobial activity against reference and
clinical strains of MRSA, with MICs ranging from 8-16 mg/L for UA to 32-128 mg/L 
for OA. They were highly synergistic with β-lactams (ampicillin and oxacillin) at
subMIC concentrations. Reversion of MRSA phenotype was attributed to their
capacity to delocalize PBP2 from the septal division site, as observed by
fluorescence microscopy, and to disturb thereby peptidoglycan synthesis.
Moreover, both compounds also inhibited β-lactamases activity of living bacteria 
(as assessed by inhibition of nitrocefin hydrolysis), but not in bacterial
lysates, suggesting an indirect mechanism for this inhibition. In a murine model 
of subcutaneous MRSA infection, local administration of UA was synergistic with
nafcillin to reduce lesion size and inflammatory cytokine (IL-1β) production.
Thus, these data highlight the potential interest of triterpenic acids as
resistance reversing agents in combination with β-lactams against MRSA.

DOI: 10.3390/molecules22122245 
PMID: 29258194 

Conflict of interest statement: The authors declare no conflict of interest.