Quantifying synergy in the bioassay-guided fractionation of natural product extracts.

Abstract

Mixtures of drugs often have greater therapeutic value than any of their constituent drugs alone, and such combination therapies are widely used to treat diseases such as cancer, malaria, and viral infections. However, developing useful drug mixtures is challenging due to complex interactions between drugs. Natural substances can be fruitful sources of useful drug mixtures because secondary metabolites produced by living organisms do not often act in isolation in vivo. In order to facilitate the study of interactions within natural substances, a new analytical method to quantify interactions using data generated in the process of bioassay-guided fractionation is presented here: the extract fractional inhibitory concentration index (EFICI). The EFICI method uses the framework of Loewe additivity to calculate fractional inhibitory concentration values by which interactions can be determined for any combination of fractions that make up a parent extract. The EFICI method was applied to data on the bioassay-guided fractionation of Lechea mucronata and Schinus terebinthifolia for growth inhibition of the pathogenic bacterium Acinetobacter baumannii. The L. mucronata extract contained synergistic interactions (EFICI = 0.4181) and the S. terebinthifolia extract was non-interactive overall (EFICI = 0.9129). Quantifying interactions in the bioassay-guided fractionation of natural substances does not require additional experiments and can be useful to guide the experimental process and to support the development of standardized extracts as botanical drugs.