Authors

Discussion

Drug resistance (DR) and drug tolerance(DT) are intrinsically different mechanisms leading to decreased drug susceptibility (measured by increase of half-maximal inhibitory concentration, IC₅₀) of pathogens. DR is a long-term adaptation acquired through genetic modification, it is heritable and high IC₅₀ persist even in the absence of drug exposure. DT is a short-term adaptation resulting from a metabolic modulation and IC₅₀ drops to low value, without drug exposure. DT is often associated with quiescence, a physiological state of cells triggered by environmental insults and involving a reversible cell division arrest driven by a dynamic and regulated cell and metabolic remodeling program. Studies on quiescence and DT in Leishmania are still in their infancy. In a previous study [Jara et al., 2022] on L. lainsoni, we developed two in vitro models of quiescence induction, under stationary starvation and Trivalent Antimonials (PAT) pressure, respectively. We found common traits (molecular and metabolic) of quiescence in both models. In a next study, we aimed to demonstrate in vitro the link between quiescence and DT in L. braziliensis. We exposed 9 strains to high doses of PAT and demonstrated that parasite survivors showed all the criteria of DT and not of DR: (i) under drug pressure, signatures of quiescence (reduced proliferation and significant decrease of rDNA transcription), (ii) the phenotype was reversible and IC₅₀ dropped back after PAT removal, (iii) and albeit there were genetic differences between pre- and post-exposure lineages of each strain, they were not consistent and no reported markers of DR were encountered. Finally, when comparing different strains, we found different levels of quiescence and DT in the L. braziliensis sample under study. We discuss how DT may hamper the clinical efficacy of drugs and why/how it should be taken into account in R&D for new anti-leishmania drugs.