Abstract
Resistance to allopurinol in zoonotic canine leishmaniasis has been recently shown to be associated with disease relapse in naturally-infected dogs. However, information regarding the formation of resistance and its dynamics is lacking. This study describes the successful in-vitro induction of allopurinol resistance in Leishmania infantum cultured under increasing drug pressure. Allopurinol susceptibility and growth rate of induced parasites were monitored over 23 weeks and parasite clones were tested at selected time points and compared to their parental lines, both as promastigotes and as amastigotes. Allopurinol resistance was formed in strains from two parasite stocks producing a 20-fold rise in IC50 along three distinct growth phases. In addition, characteristic differential clustering of single nucleotide polymorphisms (SNP) was found in drug sensitive and resistant parasite clones. Results confirm that genetic polymorphism, as well as clonal heterogeneity, contribute to in-vitro resistance to allopurinol, which is likely to occur in natural infection.
Highlights
Visceral leishmaniasis caused by the parasite Leishmania infantum is a neglected tropical disease transmitted from animal hosts to humans by sand fly bites
We have recently demonstrated that allopurinol resistant parasites can be isolated from naturally infected dogs that have developed clinical recurrence of disease during allopurinol treatment
Visceral leishmaniasis caused by Leishmania infantum is a life threatening disease, affecting humans in Europe, Asia, North Africa and Latin America, as well as domestic dogs which are the main reservoir for this infection [1, 2]
Summary
Visceral leishmaniasis caused by Leishmania infantum is a life threatening disease, affecting humans in Europe, Asia, North Africa and Latin America, as well as domestic dogs which are the main reservoir for this infection [1, 2]. We recently reported the detection of disease relapse in infected dogs associated with allopurinol resistant parasite strains [3]. Allopurinol is the main drug used for long-term control of the canine disease, and since resistant parasites may enhance transmission to humans and other dogs [4], this finding is alarming. We aimed to improve our understanding of the formation of resistance to allopurinol by following an in-vitro model of resistance induction in susceptible isolates under increasing drug pressure and examining the susceptibility to allopurinol of several clones from the same time point, in both promastigote and amastigote stages
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