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Ursolic acid from shea butter tree ( Vitellaria paradoxa ) leaf extract synergizes with β‐lactams against methicillin‐resistant Staphylococcus aureus
Author(s) -
Catteau Lucy,
Olson Joshua,
Van Bambeke Françoise,
Leclercq Joelle,
Nizet Victor
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.1000.5
Subject(s) - antimicrobial , staphylococcus aureus , ursolic acid , chemistry , minimum inhibitory concentration , traditional medicine , microbiology and biotechnology , biology , bacteria , chromatography , medicine , genetics , organic chemistry
Given the increasing emergence of antibiotic resistance, the discovery of novel therapeutic options for the treatment of infections is urgently needed. One strategy for overcoming bacterial resistance mechanisms is the use of drugs in combination, such as β‐lactams together with β‐lactamase inhibitors. Here, via a screen of direct and indirect antimicrobial activities of plants used in traditional medicine, we show that a dichloromethane extract of leaves from the shea butter tree ( Vitellaria paradoxa ) exhibited potent antimicrobial activity against methicillin‐resistant Staphylococcus aureus (MRSA), both alone and in synergistic combination with β‐lactams. Using dichloromethane extraction and an HPLC‐MS method, we detected ursolic (UA) and oleanolic acids (OA) in leaves and twigs of this species and further quantified the abundance of the two triterpenic acids by HPLC‐UV. We then compared the antimicrobial activity of crude V. paradoxa extracts against different clinical and reference strains of MRSA to that of purified UA and OA. Direct antimicrobial activity was determined as minimal inhibitory concentrations (MICs), and potential synergy with β‐lactams was assessed using checkerboard titration and calculation of fractional inhibitory concentration index (FICI), with FICI values ≤ 0.5 indicative of synergy and ≤ 1 defined as additivity. High UA (21%) and OA (6%) content correlated with the antimicrobial activity of the plant extract. UA was more active than OA, with anti‐staphylococcal MICs ranging from 8 – 32 compared to 64 – 256 μg/mL, respectively. Both triterpenic acids synergized with all three β‐lactams tested (ampicillin, oxacillin and nafcillin), indicating an activity targeting PBP2a +/− β‐lactamases. Analysis of the effects of UA and OA on host cells revealed that they inhibited reactive oxygen species production and chemotaxis of human neutrophils, with the plant extract only mimicking the inhibition of chemotaxis. UA, OA and the leaf extract also exhibited a protective effect against red blood cells hemolysis caused by MRSA and purified alpha‐toxin. Finally, we showed that local administration of UA provided a synergistic benefit to nafcillin in reducing lesion size and inflammatory cytokine (IL‐1β) production in a murine model of subcutaneous MRSA infection. Together, our findings reveal both antimicrobial and immune regulatory activities of shea butter tree leaf extract indicating its potential as a therapeutic agent for the treatment of antibiotic resistant infections and source of original lead compounds. Support or Funding Information The authors gratefully thank the Belgian Fonds de la Recherche Scientifique , the Faculty of Pharmacy and Biomedical Sciences of UCL and the Nizet lab of UCSD for financial support. Lucy Catteau has been a visiting graduate student at UCSD from June to November 2016 thanks to a Fulbright fellowship.