Abstract
Current treatment options for visceral leishmaniasis have several drawbacks, and clinicians are confronted with an increasing number of treatment failures. To overcome this, the Drugs for Neglected Diseases initiative (DNDi) has invested in the development of novel antileishmanial leads, including a very promising class of oxaboroles. The mode of action/resistance of this series to Leishmania is still unknown and may be important for its further development and implementation. Repeated in vivo drug exposure and an in vitro selection procedure on both extracellular promastigote and intracellular amastigote stages were both unable to select for resistance. The use of specific inhibitors for ABC-transporters could not demonstrate the putative involvement of efflux pumps. Selection experiments and inhibitor studies, therefore, suggest that resistance to oxaboroles may not emerge readily in the field. The selection of a genome-wide cosmid library coupled to next-generation sequencing (Cos-seq) was used to identify resistance determinants and putative targets. This resulted in the identification of a highly enriched cosmid, harboring genes of chromosome 2 that confer a subtly increased resistance to the oxaboroles tested. Moderately enriched cosmids encompassing a region of chromosome 34 contained the cleavage and polyadenylation specificity factor (cpsf) gene, encoding the molecular target of several related benzoxaboroles in other organisms.
Highlights
Visceral leishmaniasis (VL) is a disease caused by an infection with the protozoan parasites Leishmania infantum or L. donovani and results, among other symptoms, in serious anemia, wasting and hepatosplenomegaly, which can eventually be fatal when left untreated [1]
In vitro resistance selection for DNDI-6148 was found to be unsuccessful with intracellular parasites, as susceptibility did not change significantly for either the L. infantum
Since an overlapping fragment of chromosome 2 was enriched in both cosmid library screens, we looked to validate the direct role of this genomic fragment, and the genes it encodes, in resistance to DNDI-6148
Summary
Visceral leishmaniasis (VL) is a disease caused by an infection with the protozoan parasites Leishmania infantum or L. donovani and results, among other symptoms, in serious anemia, wasting and hepatosplenomegaly, which can eventually be fatal when left untreated [1]. The Leishmania parasite is transmitted to humans by sandflies, following establishment and differentiation into infective stages in the insect gut [2,3]. It is for that reason that the Drugs for Neglected Diseases initiative (DNDi) has invested in the development of novel antileishmanial drugs, with the recent discovery of promising. Microorganisms 2021, 9, 1408 preclinical leads and clinical candidates [7,8]. One of the most promising lead series is the oxaboroles, with DNDI-6148 as the frontrunner, currently in Phase I clinical trials [9,10]
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