Leishmaniasis is an infectious disease caused by parasites of the genus Leishmania. The main clinical manifestations of this infection (cutaneous, mucous, and visceral leishmaniasis) depend on several inherent factors in the infected patient and the parasite species causing the disease (World Health Organization, 2010). In Colombia, the most prevalent species are L. panamensis and L. braziliensis (Herrera et al., 2020) whose sensitivity to meglumine antimoniate (MA) is lower than other Leishmania species (Fernandez Pimentel et al., 2011).

Leishmania has a dimorphic life cycle, with the promastigote form developing in the phlebotomine vector while the amastigote forms developing in the mammalian host (Wheeler et al., 2011). The knowledge about the different forms of the parasite's adaptation to its hosts is the basis of the disease pathogenesis and the new therapies proposal. Therefore, developing better treatments is mandatory because available medicines have multiple disadvantages, such as difficult access, handling, and high toxicity resulting from antimonial-based therapies (Wheeler et al., 2011; Singh et al., 2012).

Worldwide, pentavalent antimonials are the standard drugs for treating CL. However, these drugs are often poorly tolerated because of common and sometimes severe adverse effects, development of drug resistance, and parenteral administration. Other treatment options include miltefosine (MIL), amphotericin B (AMB), pentamidine (PEN), paromomycin, and some azoles such as ketoconazole, fluconazole, and itraconazole) but also local therapies, including thermotherapy and cryotherapy (Aronson and Joya, 2019).

One of the most used approaches in searching for new drugs is rational development, where candidate drugs are selected based on a molecular target in the parasite. In Leishmania spp, numerous molecular targets have been explored in diverse metabolic pathways, allowing novel candidate drugs to be generated; some are already in advanced stages of development. However, none of these candidates have been introduced into the market. Therefore, searching for molecules with antileishmanial activity is still needed.

The l-arginine is the precursor of polyamine and trypanothione synthesis. Both are molecules with high importance in the Leishmania species' biological processes of growth and infectivity in vitro. l-arginine participates in the leishmanicidal action of the macrophage through nitric oxide (NO) production, which has been linked to the death of the parasite due to oxidative stress (Wanasen and Soong, 2008; Mandal et al., 2016; Colotti and Ilari, 2011; Nayak et al., 2018; Muxel et al., 2018). Based on these findings and others not reviewed here, we proposed the metabolism of l-arginine as a potential source in the search for new therapeutic targets for the leishmaniasis treatment.

This work evaluated the effects of changes in the extracellular concentration of l-Arg in different L. braziliensis physiological processes such as replication, stage differentiation, and infectivity. The effect of l-arginine concentrations on the sensitivity of L. braziliensis to antileishmanial drugs MA, PEN, MIL, and AMB, and reactive oxygen species (ROS) generation was also determined to identify a link between l-arginine metabolism and the mode of action of antileishmanial drugs and, therefore, to determine the potential of l-arginine as a therapeutic target.