Antimony Resistance in Leishmania Parasites may be
Related to an Increased Virulence
Chemotherapy is the main approach for leishmaniasis management, and antimonial
(Meglumine antimoniate and Sodium stibogluconate) are the first class of drugs applied
to leishmaniasis treatment. Treatment with these drugs has several limitations, including
the progressive emergence of resistant parasites. Aggravating this situation, recent
evidence that the antimonial resistance and virulence may be correlated in Leishmania
sp. have been published in the literature, and this may contribute to the severity of the
disease, directly reflecting on the prognosis of infected patients. The correlation between
Leishmania virulence and antimony resistance parameters is not fully understood yet,
but due to its clinical relevance, it is critically necessary further enlighten this fact.
The leishmaniasis are complex heterogenic vector-borne
diseases caused by Leishmania spp. (Protozoa, Kinetoplastida,
Trypanosomatidae) and spread by female sand flies .
Chemotherapy is the main approach for leishmaniasis management.
However, the combined problems of parenteral administration
and anti-leishmaniasis substantial side effects are factors that
hinder treatment. In addition, the selection of resistant parasites
carrying genetic mutations that lessen the parasite’s response
to drugs may emerge upon mass drug administration . There
are only a few drugs available for leishmaniasis treatment and
most of them have been in use for quite some time. Pentavalent
antimonial, amphotericin B, pentamidine, miltefosine and
paromomycin constitute the resources available for leishmaniasis
chemotherapy . Antimonial (Meglumine antimoniate and Sodium
stibogluconate) are the first class of drugs applied to leishmaniasis
treatment. These toxic compounds have a narrow therapeutic
window but are still in use in various regions of the world such as
Latin America and East Africa [2,3].
Another complicating factor includes the fact that Leishmania
parasites present the possibility of suffering considerable genomic
changes, such as chromosomal aneuploidies, and changes in gene
expression pattern, which appear to be involved in the adaptation
of these organisms to the presence of the drug. Over the last 10
to 20 years, there has been an increased in clinical resistance
to antimonial, which has even led to the abolition of use in some
regions, for example, in North Bihar in India . Some studies on
prokaryotes and eukaryotes show that drug resistance is usually
related to a reduction in the fitness of microorganisms, since there
is a decrease in growth, virulence and transmissibility between
hosts [4,5]. However, it has recently been observed that some
species of Leishmania, especially L. donovani, resistant to antimonial
appear to have developed a series of molecular adaptations that
lead to an increased parasite fitness even in the absence of the
drug. This ability has been related to the competence to generate
metacyclic forms, which have greater power of host infection. The
plastic nature of the genome of these parasites makes them highly adaptable, being able to modulate gene expression through gene
amplification or deletion and alter chromosomal ploidy in response
to drug-stress [6-9].
Vanaerschot and collaborators  analyzed antimonial
susceptible and resistant clinical isolates of L. donovani. The
authors observed that resistant parasites showed lower sensitivity
to oxidative and Nitrosative stress in vitro. The in vitro macrophage
infection rate was significantly higher in drug-resistant strains and
they were also more infective in vivo, reaching a higher parasitic
load in both spleen and liver of infected Balb/c mice. The authors
suggest that higher stress resistance and a greater number of
metacyclic forms may contribute to resistant strains had superior
survival skills as promastigotes and as amastigotes compared to
the sensitive’s strains. Ouakad and colleagues  demonstrated
that antimony-resistant L. donovani strains had twice as many
metacyclic forms as those found in antimony-sensitive cultures.
Resistant cultures also had higher infection capacity in murine
macrophages and were more resistant to complement-mediated
lysis. Another study also analyzed antimony-resistant L. donovani
strains found higher in vivo infection power . Another research,
by Moura and colleagues , used L. infantum strains isolated from
refractory patients to antimony treatment (relapse cases) and
responsive patients (control group). Macrophage infection was
higher with L. infantum isolates from relapse cases and correlated
with enhanced interleukin 1-β production, furthermore, these
parasites stimulated inflammatory cytokines and were resistant
to macrophage killing mechanisms, factors that may contribute to
Findings between the possible correlation of increased
virulence in antimonial-resistant Leishmania parasites raise a
fundamental question about potential risks of selecting more
virulent pathogens through massive chemotherapy interventions.
Further work is needed to further clarify this fact and to lead to
better guidelines for the treatment of these disorders.
- Bates PA (2018) Revising Leishmania’s life cycle. Nature microbiology 3(5): 529-530.
- Ponte Sucre A, Gamarro F, Dujardin J, Barrett MP, López Vélez R, et al. (2017) Drug resistance and treatment failure in leishmaniasis: A 21st century challenge. Plos Negl Trop Dis 11(12): e0006052.
- Uliana SRB, Trinconi CT, Coelho AC (2017) Chemotherapy of leishmaniasis: present challenges. Parasitology 145(4): 464-480.
- Babiker HA, Hastings IM, Swedberg G (2009) Impaired fitness of drug-resistant Malaria parasites: evidence and implication on drug-deployment policies. Expert Rev Anti Infe 7(5): 581-593.
- Abdelraouf K, Kabbara S, Ledesma KR, Poole K, Tam VH (2011) Effect of multidrug resistance-conferring mutations on the fitness and virulence of Pseudomonas aeruginosa. J Antimicrob Chemother 66(6): 1311-1317.
- Vanaerschot M, Maes I, Ouakad M, Adaui V, Maes L, et al. (2010) Linking in vitro and in vivo survival of clinical Leishmania donovani Plos one 5(8): e12211.
- Ouakad M, Vanaerschot M, Rijal S, Sundar S, Speybroeck N, et al. (2011) Increased metacyclogenesis of antimony-resistant Leishmania donovani clinical lines. Parasitology 138(11): 1392-1399.
- Vanaerschot M, Doncker S, Rijal S, Maes L, Dujardin JC, et al. (2011) Antimonial resistance in Leishmania donovani is associated with increased in vivo parasite burden. Plos One 6(8): e23120.
- Moura TR, Santos MLB, Braz JM, Santos LF, Aragão MT, et al. (2016) Cross-resistance of Leishmania infantum isolates to nitric oxide from patients refractory to antimony treatment and greater tolerance to antileishmanial responses by macrophages. Parasitol Res 115(2): 713-721.