Molecular Preadaptation to Antimony Resistance in Leishmania donovani on the Indian Subcontinent

• DOI: 10.1128/msphere.00548-17
• Publication Date: 2018-04-17T09:54:03Z
• Authors: F. Dumetz; B. Cuypers; H. Imamura; D. Zander; E. D’Haenens; I. Maes; M. A. Domagalska; J. Clos; J.-C. Dujardin; G. De Muylder
• Keywords: Indian subcontinent

Antimonials (Sb) were used for decades chemotherapy of visceral leishmaniasis (VL). Now abandoned in the Indian subcontinent (ISC) because Leishmania donovani resistance, this drug offers a unique model understanding resistance dynamics. In previous phylogenomic study, we found two distinct populations L. donovani: core group (CG) Gangetic plains and ISC1 Nepalese highlands. Sb was only encountered within CG, series potential markers identified. Here, analyzed development to trivalent antimonials (SbIII) upon experimental selection CG strains. We observed that (i) baseline SbIII susceptibility parasites higher than (ii) time strains, (iii) untargeted genomic metabolomic analyses revealed molecular changes along process: these more numerous CG. Altogether observations led hypothesis are preadapted resistance. This experimentally confirmed by showing wild-type strains could survive direct exposure maximal concentration The main driver preadaptation shown be MRPA, gene involved sequestration amplified an intrachromosomal amplicon all characterized so far. emerged around 1850 well before implementation VL chemotherapy, discuss here several hypotheses selective pressure have accompanied its emergence.IMPORTANCE "antibiotic crisis" is major challenge scientists medical professionals. steady rise drug-resistant pathogens also extends parasitic diseases, with antimony being first anti-Leishmania fell (ISC). Leishmaniasis but neglected infectious disease limited therapeutic options. Therefore, how became resistant commanding importance. dynamics acquisition show some ISC likely driven environmental factors or drugs 19th century.