Resistance to Antileishmanial Drug Candidates: A Flowchart for an Early Phenotypic Evaluation of Risk

Background: Drug development for leishmaniases treatment follows a very selective process in order to propose drug candidates that possess all the qualities that meet the strict specifications of the pharmaceutical industry. Drug resistance is a limiting factor that can impact the lifespan of a marketed drug. It is now essential that the risk of drug resistance be evaluated at the early stage of in vitro studies to discard a lead compound that could quickly generate drug resistance once available on the market. Objectives: This article aims to estimate the risk of drug resistance emergence for a promising drug candidate at the in vitro early stage of drug development. Methods: A sequential method is proposed to study some of the phenotypic characteristics and parameters of resistant parasites such as time to achieve maximal resistance during stepwise drug pressure, resistance amplitude, stability, fitness, and infectivity both in vitro and in vivo. Results: Some examples with drugs in clinical use and former drug candidates are given. Conclusions: This method providing an evaluation of the risk of drug resistance from an in vitro model of Leishmania donovani be extrapolated to other Leishmania species.