Abstract
Antimonials (Sb) were used for decades for chemotherapy of visceral leishmaniasis (VL). Now abandoned in the Indian subcontinent (ISC) because of Leishmania donovani resistance, this drug offers a unique model for understanding drug resistance dynamics. In a previous phylogenomic study, we found two distinct populations of L.donovani: the core group (CG) in the Gangetic plains and ISC1 in the Nepalese highlands. Sb resistance was only encountered within the CG, and a series of potential markers were identified. Here, we analyzed the development of resistance to trivalent antimonials (SbIII) upon experimental selection in ISC1 and CG strains. We observed that (i) baseline SbIII susceptibility of parasites was higher in ISC1 than in the CG, (ii) time to SbIII resistance was higher for ISC1 parasites than for CG strains, and (iii) untargeted genomic and metabolomic analyses revealed molecular changes along the selection process: these were more numerous in ISC1 than in the CG. Altogether these observations led to the hypothesis that CG parasites are preadapted to SbIII resistance. This hypothesis was experimentally confirmed by showing that only wild-type CG strains could survive a direct exposure to the maximal concentration of SbIII The main driver of this preadaptation was shown to be MRPA, a gene involved in SbIII sequestration and amplified in an intrachromosomal amplicon in all CG strains characterized so far. This amplicon emerged around 1850 in the CG, well before the implementation of antimonials for VL chemotherapy, and we discuss here several hypotheses of selective pressure that could have accompanied its emergence.IMPORTANCE The "antibiotic resistance crisis" is a major challenge for scientists and medical professionals. This steady rise in drug-resistant pathogens also extends to parasitic diseases, with antimony being the first anti-Leishmania drug that fell in the Indian subcontinent (ISC). Leishmaniasis is a major but neglected infectious disease with limited therapeutic options. Therefore, understanding how parasites became resistant to antimonials is of commanding importance. In this study, we experimentally characterized the dynamics of this resistance acquisition and show for the first time that some Leishmania populations of the ISC were preadapted to antimony resistance, likely driven by environmental factors or by drugs used in the 19th century.
Highlights
Antimonials (Sb) were used for decades for chemotherapy of visceral leishmaniasis (VL)
The study highlighted a series of features relevant in the context of Sb resistance. (i) All 191 isolates (Sb-R or Sb sensitive [Sb-S]) from the core group (CG) harbored two intrachromosomal amplifications (ICAs) of sets of adjacent genes, called the M and H loci; these genes were not amplified in isolates from the ISC1 subpopulation
The H locus was reported elsewhere to be a major driver of SbIII resistance because of the presence of one gene, MRPA, encoding a member of the multidrug resistance protein family that sequesters Sb-thiol complexes into intracellular vesicles [10,11,12]. (ii) Within the CG, a particular genetic group, ISC5, concentrates most of the strains isolated from antimonial treatment failure patients
Summary
Antimonials (Sb) were used for decades for chemotherapy of visceral leishmaniasis (VL). IMPORTANCE The “antibiotic resistance crisis” is a major challenge for scientists and medical professionals This steady rise in drug-resistant pathogens extends to parasitic diseases, with antimony being the first anti-Leishmania drug that fell in the Indian subcontinent (ISC). The study described a natural history frame for the VL epidemics: the main population of L. donovani emerged about 150 years ago in northeast India, and after a succession of bottlenecks and expansions, it generated a series of subpopulations, currently defined as ISC2 to ISC10 and gathered within a main core group (CG) Another genetic group (ISC1), which diverged much earlier from the CG, was discovered in the highlands of Nepal. All 52 strains of that group harbor a 2-nucleottide (nt) insertion in the AQP1 gene, creating a nonfunctional variant of this transporter known to be involved in the uptake of SbIII [13, 14]. (iii) Other genomic adaptations to SbIII, involved in detoxification mechanisms and increased levels of thiols reported in experimental resistance [15], had not been encountered (yet) in the natural population under study
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
