Global distribution of treatment resistance gene markers for leishmaniasis

Salari, Samira; Bamorovat, Mehdi; Sharifi, Iraj; Almani, Pooya Ghasemi Nejad

doi:10.1002/jcla.24599

Cited by 25 publications

(12 citation statements)

References 167 publications

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“…Many patients' incorrect antimonial therapy causes pharmacological stress on the parasite organisms, resulting in adaptation and, finally, persistence against Sb(V). 103,104 The gradual evolution of antimony resistance raises the notion that numerous mutations need to occur to produce a resistant phenotype. Several in vitro processes may clarify the reported antimonial resistance, albeit it should be noted that the in vitro response is not always translated into clinical resistance.…”

Section: Drug Resistance Linked To Mutationmentioning

confidence: 99%

Genomic Insight of Leishmania Parasite: In-Depth Review of Drug Resistance Mechanisms and Genetic Mutations

Bharadava,

Upadhyay,

Kaushal

et al. 2024

ACS Omega

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Leishmaniasis, which is caused by a parasitic protozoan of the genus Leishmania, is still a major threat to global health, impacting millions of individuals worldwide in endemic areas. Chemotherapy has been the principal method for managing leishmaniasis; nevertheless, the evolution of drug resistance offers a significant obstacle to therapeutic success. Drug-resistant behavior in these parasites is a complex phenomenon including both innate and acquired mechanisms. Resistance is frequently related to changes in drug transportation, drug target alterations, and enhanced efflux of the drug from the pathogen. This review has revealed specific genetic mutations in Leishmania parasites that are associated with resistance to commonly used antileishmanial drugs such as pentavalent antimonials, miltefosine, amphotericin B, and paromomycin, resulting in changes in gene expression along with the functioning of various proteins involved in drug uptake, metabolism, and efflux. Understanding the genetic changes linked to drug resistance in Leishmania parasites is essential for creating approaches for tackling and avoiding the spread of drug-resistant variants. Based on which specific treatments focus on mutations and pathways could potentially improve treatment efficacy and help long-term leishmaniasis control. More study is needed to uncover the complete range of genetic changes generating medication resistance and to develop new therapies based on available information.

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Section: Drug Resistance Linked To Mutationmentioning

confidence: 99%

Genomic Insight of Leishmania Parasite: In-Depth Review of Drug Resistance Mechanisms and Genetic Mutations

Bharadava,

Upadhyay,

Kaushal

et al. 2024

ACS Omega

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“…An increase in the clinical availability and use of antileishmanial drugs has been observed in recent years, with a positive impact observed in the reduced severity of disease especially in the most lethal visceral leishmaniasis manifestation [10]. Such treatment of leishmaniasis still presents with the classical challenges of any drug treatments, including the emergence of drug resistant parasites [11], however, and prevention through immunization appears both attainable and preferred. Unfortunately, despite the plethora of preclinical evaluations multiple factors have precluded advancement of more than a few Leishmania targeting vaccines to clinical trial.…”

Section: Potential Application Of Rna Technology For Leishmania Vaccinesmentioning

confidence: 99%

Leishmaniasis Vaccines: Applications of RNA Technology and Targeted Clinical Trial Designs

et al. 2022

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Leishmania parasites cause a variety of discrete clinical diseases that present in regions where their specific sand fly vectors sustain transmission. Clinical and laboratory research indicate the potential of immunization to prevent leishmaniasis and a wide array of vaccine candidates have been proposed. Unfortunately, multiple factors have precluded advancement of more than a few Leishmania targeting vaccines to clinical trial. The recent maturation of RNA vaccines into licensed products in the context of COVID-19 indicates the likelihood of broader use of the technology. Herein, we discuss the potential benefits provided by RNA technology as an approach to address the bottlenecks encountered for Leishmania vaccines. Further, we outline a variety of strategies that could be used to more efficiently evaluate Leishmania vaccine efficacy, including controlled human infection models and initial use in a therapeutic setting, that could prioritize candidates before evaluation in larger, longer and more complicated field trials.

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“…Leishmaniasis is a neglected tropical disease (NTD) caused by Leishmania parasites, a type of trypanosomatid protozoa [ 1 ]. The disease affects 15 million people globally, presenting in three forms: cutaneous (CL), mucocutaneous (ML), and visceral (VL) [ 2 , 3 ]. Despite public health concerns and the need for control, current treatments, including pentavalent antimony salts as first-line drugs or amphotericin B, pentamidine, miltefosine, or paromomycin as second-line drugs, are frequently toxic, as well as expensive with increasing resistance outbreak [ 3 , 4 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

“…The disease affects 15 million people globally, presenting in three forms: cutaneous (CL), mucocutaneous (ML), and visceral (VL) [ 2 , 3 ]. Despite public health concerns and the need for control, current treatments, including pentavalent antimony salts as first-line drugs or amphotericin B, pentamidine, miltefosine, or paromomycin as second-line drugs, are frequently toxic, as well as expensive with increasing resistance outbreak [ 3 , 4 , 5 ]. Liposomal amphotericin B is one of the best treatment options for leishmaniasis, but its effectiveness depends on the patient’s immune status, clinical presentation, and location.…”

Section: Introductionmentioning

confidence: 99%

Kaurane-Type Diterpenoids as Potential Inhibitors of Dihydrofolate Reductase-Thymidylate Synthase in New World Leishmania Species

et al. 2023

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The bifunctional enzyme Dihydrofolate reductase-thymidylate synthase (DHFR-TS) plays a crucial role in the survival of the Leishmania parasite, as folates are essential cofactors for purine and pyrimidine nucleotide biosynthesis. However, DHFR inhibitors are largely ineffective in controlling trypanosomatid infections, largely due to the presence of Pteridine reductase 1 (PTR1). Therefore, the search for structures with dual inhibitory activity against PTR1/DHFR-TS is crucial in the development of new anti-Leishmania chemotherapies. In this research, using the Leishmania major DHFR-TS recombinant protein, enzymatic inhibitory assays were performed on four kauranes and two derivatives that had been previously tested against LmPTR1. The structure 302 (6.3 µM) and its derivative 302a (4.5 µM) showed the lowest IC50 values among the evaluated molecules. To evaluate the mechanism of action of these structures, molecular docking calculations and molecular dynamics simulations were performed using a DHFR-TS hybrid model. Results showed that hydrogen bond interactions are critical for the inhibitory activity against LmDHFR-TS, as well as the presence of the p-hydroxyl group of the phenylpropanoid moiety of 302a. Finally, additional computational studies were performed on DHFR-TS structures from Leishmania species that cause cutaneous and mucocutaneous leishmaniasis in the New World (L. braziliensis, L. panamensis, and L. amazonensis) to explore the targeting potential of these kauranes in these species. It was demonstrated that structures 302 and 302a are multi-Leishmania species compounds with dual DHFR-TS/PTR1 inhibitory activity.

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Global distribution of treatment resistance gene markers for leishmaniasis

Cited by 25 publications

References 167 publications

Genomic Insight of Leishmania Parasite: In-Depth Review of Drug Resistance Mechanisms and Genetic Mutations

Genomic Insight of Leishmania Parasite: In-Depth Review of Drug Resistance Mechanisms and Genetic Mutations

Leishmaniasis Vaccines: Applications of RNA Technology and Targeted Clinical Trial Designs

Kaurane-Type Diterpenoids as Potential Inhibitors of Dihydrofolate Reductase-Thymidylate Synthase in New World Leishmania Species

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