Of Drugs and Trypanosomatids: New Tools and Knowledge to Reduce Bottlenecks in Drug Discovery

Bhattacharya, A. R.; Corbeil, Audrey; Monte-Neto, Rubens L.; Fernández-Prada, Christopher

doi:10.3390/genes11070722

Cited by 32 publications

(33 citation statements)

References 162 publications

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“…In addition to CNVs, single-nucleotide polymorphisms (SNPs) in drug target genes or in transporters can lead to drug resistance without the need for altering gene content [22,23,24]. Markedly, recent studies point to the need for experimental generation of drug-resistance to promising compounds in order to clinically evaluate and eventually circumvent the phenomenon [25,26,27].…”

Section: Discussionmentioning

confidence: 99%

Three Different Mutations in the DNA Topoisomerase 1B in Leishmania Infantum Contribute to Resistance to Antitumor Drug Topotecan

Rosa-Teijeiro

Wagner

Corbeil

et al. 2021

Preprint

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BackgroundThe evolution of drug resistance is one of the biggest challenges in leishmaniasis and has prompted the need for new antileishmanial drugs. Repurposing of approved drugs is a faster and very attractive strategy that is gaining supporters worldwide. Different anticancer topoisomerase 1B (TOP1B) inhibitors have shown strong antileishmanial activity and promising selective indices, supporting the potential repurposing of these drugs. However, cancer cells and Leishmania share the ability to become rapidly resistant. The aim of this study was to complete a whole-genome exploration of the effects caused by exposure to topotecan in order to highlight the potential mechanisms deployed by Leishmania to favor its survival in the presence of a TOP1B inhibitor. MethodsWe used a combination of stepwise drug-resistance selection, whole-genome sequencing, functional validation, and theoretical approaches to explore the propensity of and potential mechanisms deployed by three independent clones of L. infantum to resist the action of TOP1B-inhibitor topotecan. ResultsWe demonstrated that L. infantum is capable of becoming resistant to high concentrations of topotecan without impaired growth ability. No gene deletions or amplifications were identified from the next-generation sequencing data in any of the three resistant lines, ruling out the overexpression of efflux pumps as the preferred mechanism of topotecan resistance. We identified three different mutations in the large subunit of the leishmanial TOP1B (Top1BF187Y, Top1BG191A and Top1BW232R). Overexpression of these mutated alleles in the wild-type background led to high levels of resistance to topotecan. Computational molecular dynamics simulations, in both covalent and non-covalent complexes, showed that these mutations have an effect on the arrangement of the catalytic pentad and on the interaction of these residues with surrounding amino acids and DNA. This altered architecture of the binding pocket results in decreased persistence of topotecan in the ternary complex. ConclusionsThis work helps elucidate the previously-unclear potential mechanisms of topotecan resistance in Leishmania by mutations in the large subunit of TOP1B and provides a valuable clue for the design of improved inhibitors to combat resistance in both leishmaniasis and cancer. Our data highlights the importance of including drug-resistance evaluation in drug-discovery cascades.

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Section: Discussionmentioning

confidence: 99%

Three Different Mutations in the DNA Topoisomerase 1B in Leishmania Infantum Contribute to Resistance to Antitumor Drug Topotecan

Rosa-Teijeiro

Wagner

Corbeil

et al. 2021

Preprint

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“…However, many compounds have been evaluated in forms of the free-living parasites, such as promastigotes and trypomastigotes, or axenic amastigotes, an unnatural extracellular form created under laboratory conditions, that can detect very preliminary antiprotozoal activity or simple cytotoxicity ( Table 1 ) [ 9 ]. Therefore, it is necessary to culture mammalian cells infected in vitro with the pathogen, and, thus, the toxicity of the drug towards cells and its ability to be selective towards the parasites is known [ 125 ]. However, after a drug has demonstrated potential antiparasitic activity, its mechanism of action must be known, so target-based assays are indispensable.…”

Section: Future Microbial Metabolitesmentioning

confidence: 99%

Microorganisms as a Potential Source of Molecules to Control Trypanosomatid Diseases

et al. 2021

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Trypanosomatids are the causative agents of leishmaniasis and trypanosomiasis, which affect about 20 million people in the world’s poorest countries, leading to 95,000 deaths per year. They are often associated with malnutrition, weak immune systems, low quality housing, and population migration. They are generally recognized as neglected tropical diseases. New drugs against these parasitic protozoa are urgently needed to counteract drug resistance, toxicity, and the high cost of commercially available drugs. Microbial bioprospecting for new molecules may play a crucial role in developing a new generation of antiparasitic drugs. This article reviews the current state of the available literature on chemically defined metabolites of microbial origin that have demonstrated antitrypanosomatidactivity. In this review, bacterial and fungal metabolites are presented; they originate from a range of microorganisms, including cyanobacteria, heterotrophic bacteria, and filamentous fungi. We hope to provide a useful overview for future research to identify hits that may become the lead compounds needed to accelerate the discovery of new drugs against trypanosomatids.

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“…The chemotherapy of leishmaniasis is based on the use of sodium stibogluconate, meglumine antimoniate, pentamidine, amphotericin B, paromomycin, and miltefosine. These drugs are toxic and have other limitations such as the route of administration, length and cost of treatment, and emergence of drug resistance [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Antiprotozoal Compounds from Urolepis hecatantha (Asteraceae)

Elso

Clavin

Hernández

et al. 2021

Evidence-Based Complementary and Alternative Medicine

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The dewaxed dichloromethane extract of Urolepis hecatantha and the compounds isolated from it were tested for their in vitro activity on Trypanosoma cruzi epimastigotes and Leishmania infantum promastigotes. The extract of U. hecatantha showed activity against both parasites with IC50 values of 7 µg/mL and 31 µg/mL, respectively. Fractionation of the dichloromethane extract led to the isolation of euparin, jaceidin, santhemoidin C, and eucannabinolide. The sesquiterpene lactones eucannabinolide and santhemoidin C were active on T. cruzi with IC50 values of 10 ± 2 µM (4.2 µg/mL) and 18 ± 3 µM (7.6 µg/mL), respectively. Euparin and santhemoidin C were the most active on L. infantum with IC50 values of 18 ± 4 µM (3.9 µg/mL) and 19 ± 4 µM (8.0 µg/mL), respectively. Eucannabinolide has also shown drug-like pharmacokinetic and toxicity properties.

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Of Drugs and Trypanosomatids: New Tools and Knowledge to Reduce Bottlenecks in Drug Discovery

Cited by 32 publications

References 162 publications

Three Different Mutations in the DNA Topoisomerase 1B in Leishmania Infantum Contribute to Resistance to Antitumor Drug Topotecan

Three Different Mutations in the DNA Topoisomerase 1B in Leishmania Infantum Contribute to Resistance to Antitumor Drug Topotecan

Microorganisms as a Potential Source of Molecules to Control Trypanosomatid Diseases

Antiprotozoal Compounds from Urolepis hecatantha (Asteraceae)

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