Planta Med 2014; 80 - P1M3
DOI: 10.1055/s-0034-1394570

Experimental design optimization of antimicrobial mixtures of active VOCs

D Stien 1, 2, E Houël 3, AMS Rodrigues 1, C Makerri 1, G Odonne 4, V Eparvier 1
  • 1CNRS – Institut de Chimie des Substances Naturelles, 91198 Gif-sur-Yvette, France
  • 2CNRS, UPMC, Observatoire Océanologique de Banyuls-sur-Mer, 66650 Banyuls-sur-Mer, France
  • 3UMR Ecofog, Institut Pasteur de la Guyane, 97300 Cayenne, France
  • 4CNRS Guyane, av. G. Charlery, 97300 Cayenne, France

In this beginning of the 21st century, a child dies from malaria every minute in Sub-Saharan Africa and tuberculosis kills every 20 seconds [1]. Also, the hidden burden of chronic viral infections such as HIV and hepatitis B and C is sobering, affecting at least 1 in 20 people globally. In fact, many authors believe that humanity is on the verge of a post-antibiotic era [2]. We believe that something different has to be brought into the scientific debate around anti-infective agents. Our opinion is that natural synergistic mixtures, which have been protecting plants for ages, can inspire the discovery of synergistic pharmaceutical preparations. As a first model approach, a set of 66 essential oils has been analysed by GC-MS and tested (Minimal Inhibitory Concentration, MIC) against pathogenic yeasts Candida albicans and C. parapsilosis. A comparative holistic analysis of the dataset allowed us to identify 6 candidate anticandidal agents: Z-ligustilide, eugenol, eugenyl acetate, citral (mixture of geranial and neral), thymol, and β-citronellol. These compounds were combined following a full factorial experimental design approach in order to optimize the anticandidal selectivity index (SI = IC50 (MRC5 cells)/MIC) of the reconstituted mixtures. It was found that Z-ligustilide and eugenol are the two main factors that most contribute to the increase of the SI, while significantly positive interaction effect was recorded for these two compounds (Fig. 1). A positive interaction effect was also detected between citral and both Z-ligustilide and eugenol. These 3 plant defence compounds can therefore be used to construct anticandidal mixtures.

Fig. 1: Main effect plot and full interaction plot matrix for mixtures selectivity indexes.

Acknowledgements: This work has benefited from an “Investissement d'Avenir” grant managed by Agence Nationale de la Recherche (CEBA, ref. ANR-10-LABX-25 – 01).

Keywords: Design of experiment, Antimicrobials, Bio-inspiration, Synergies, Selectivities.

References:

[1] Davies GR, Hope W, Khoo S. The pharmacometrics of infectious disease. CPT: Pharmacometrics Syst Pharmacol 2013; 2: e70.

[2] Kåhrström CT. Entering a post-antibiotic era? Nat Rev Microbiol 2013; 11:146.