Impact of Genetic Diversity and Genome Plasticity of Leishmania spp. in Treatment and the Search for Novel Chemotherapeutic Targets

Abstract

Leishmaniasis is one of the major public health concerns in Latin America, Africa, Asia, and Europe. The absence of vaccines for human use and the lack of effective vector control programs make chemotherapy the main strategy to control all forms of the disease. However, the high toxicity of available drugs, limited choice of therapeutic agents, and occurrence of drug-resistant parasite strains are the main challenges related to chemotherapy. Currently, only a small number of drugs are available for leishmaniasis treatment, including pentavalent antimonials (SbV), amphotericin B and its formulations, miltefosine, paromomycin sulphate, and pentamidine isethionate. In addition to drug toxicity, therapeutic failure of leishmaniasis is a serious concern. The occurrence of drug-resistant parasites is one of the causes of therapeutic failure and is closely related to the diversity of parasites in this genus. Owing to the enormous plasticity of the genome, resistance can occur by altering different metabolic pathways, demonstrating that resistance mechanisms are multifactorial and extremely complex. Genetic variability and genome plasticity cause not only the available drugs to have limitations, but also make the search for new drugs challenging. Here, we examined the biological characteristics of parasites that hinder drug discovery.

The Anti-Leishmania amazonensis and Anti-Leishmania chagasi Action of Copper(II) and Silver(I) 1,10-Phenanthroline-5,6-dione Coordination Compounds

“…The difference in susceptibility between L. amazonensis and L. chagasi to the test compounds may be a phenotype associated with the intrinsic characteristics of the Leishmania species [ 34 ]. Owing to the enormous genetic variability and plasticity of the genome in the Leishmania genus, alterations in different metabolic pathways are frequent and are related to varied responses to the same drug as well as therapeutic failures [ 35 ]. In this sense, the differences observed in cell metabolism and mitochondrial activity may be related to the particular characteristics of each Leishmania species, which will help in a greater or lesser response to different environmental changes.…”

Amphotericin B resistance correlates with increased fitness in vitro and in vivo in Leishmania (Mundinia) martiniquensis

“…The difference in the level of resistance between the AmpBRP2 and AmpBRP2i is not associated with the absence of drug pressure during the passage in the animal since AmpBRP2 was maintained in vitro in a drug-free medium for 40 passages before the injection to the mouse. Leishmania genomic plasticity may account for this result as drug resistance (reviewed by Rastrojo et al, 2018;Santi and Murta, 2022) and long-term culture (Dumetz et al, 2017;Prieto Barja et al, 2017)…”

“…The difference in the level of resistance between the AmpBRP2 and AmpBRP2i is not associated with the absence of drug pressure during the passage in the animal since AmpBRP2 was maintained in vitro in a drug-free medium for 40 passages before the injection to the mouse. Leishmania genomic plasticity may account for this result as drug resistance (reviewed by Rastrojo et al, 2018 ; Santi and Murta, 2022 ) and long-term culture ( Dumetz et al, 2017 ; Prieto Barja et al, 2017 ) has been associated with chromosome and gene copy number variations or down-regulation of genes. In AmpB-resistant L. donovani parasites generated in vitro, chromosome 29 for which many transcripts were overexpressed is co-amplified with chromosomes 5 and 26 ( Rastrojo et al, 2018 ) previously associated with fast growth in culture ( Dumetz et al, 2017 ; Prieto Barja et al, 2017 ).…”

Draft genomes of Blastocystis subtypes from human samples of Colombia

“…[46], and Entamoeba [47]. Moreover, the wide variety of hosts and the hostile environmental changes to which these microorganisms are subjected during their transmission facilitates plasticity [48] and genetic variability, as has been observed in trypanosomatid parasites such as Leishmania [49] and Trypanosoma cruzi [50,51], or even in other stramenopiles [52]. Similarly, the large number of SNPs found among the genomes subtyped as ST1 with respect to the reference supports the idea of intra-ST variation, as has been reported for assemblages of Giardia intestinalis isolates [53].…”