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Molecules 2017, 22(12), 2245; https://doi.org/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

1
Pharmacognosy Research Group, Louvain Drug Research Institute, Université catholique de Louvain, 1200 Brussels, Belgium
2
Cellular and Molecular Pharmacology Research Group, Louvain Drug Research Institute, Université catholique de Louvain, 1200 Brussels, Belgium
3
Bacterial Cell Biology Laboratory, Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, 2780-157 Oeiras, Portugal
4
Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093-0760, USA
5
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093-0760, USA
6
MASSMET Platform, Louvain Drug Research Institute, Université catholique de Louvain, 1200 Brussels, Belgium
*
Author to whom correspondence should be addressed.
Received: 2 November 2017 / Revised: 8 December 2017 / Accepted: 12 December 2017 / Published: 16 December 2017
(This article belongs to the Section Natural Products Chemistry)
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Abstract

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. View Full-Text
Keywords: Vitellaria paradoxa; ursolic acid; oleanolic acid; triterpenic acid; MRSA; β-lactamases; PBP2; skin infection Vitellaria paradoxa; ursolic acid; oleanolic acid; triterpenic acid; MRSA; β-lactamases; PBP2; skin infection
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Catteau, L.; Reichmann, N.T.; Olson, J.; Pinho, M.G.; Nizet, V.; Van Bambeke, F.; Quetin-Leclercq, J. 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. Molecules 2017, 22, 2245.

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