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Molecules (Basel, Switzerland) Sep 2023It is estimated that 250 million people worldwide are affected by schistosomiasis. Disease transmission is related to the poor sanitation and hygiene habits that affect... (Review)
Review
It is estimated that 250 million people worldwide are affected by schistosomiasis. Disease transmission is related to the poor sanitation and hygiene habits that affect residents of impoverished regions in tropical and subtropical countries. The main species responsible for causing disease in humans are , , and , each with different geographic distributions. Praziquantel is the drug predominantly used to treat this disease, which offers low effectiveness against immature and juvenile parasite forms. In addition, reports of drug resistance prompt the development of novel therapeutic approaches. Natural products represent an important source of new compounds, especially those obtained from plant sources. This review compiles data from several in vitro and in vivo studies evaluating various compounds and essential oils derived from plants with cercaricidal and molluscicidal activities against both juvenile and adult forms of the parasite. Finally, this review provides an important discussion on recent advances in molecular and computational tools deemed fundamental for more rapid and effective screening of new compounds, allowing for the optimization of time and resources.
Topics: Humans; Animals; Anthelmintics; Schistosoma haematobium; Biological Products; Schistosomiasis; Praziquantel; Schistosoma mansoni
PubMed: 37836650
DOI: 10.3390/molecules28196807 -
ELife Nov 2023accounts for the majority of over 600,000 malaria-associated deaths annually. Parasites resistant to nearly all antimalarials have emerged and the need for drugs with...
accounts for the majority of over 600,000 malaria-associated deaths annually. Parasites resistant to nearly all antimalarials have emerged and the need for drugs with alternative modes of action is thus undoubted. The FK506-binding protein FKBP35 has gained attention as a promising drug target due to its high affinity to the macrolide compound FK506 (tacrolimus). Whilst there is considerable interest in targeting FKBP35 with small molecules, a genetic validation of this factor as a drug target is missing and its function in parasite biology remains elusive. Here, we show that limiting FKBP35 levels are lethal to and result in a delayed death-like phenotype that is characterized by defective ribosome homeostasis and stalled protein synthesis. Our data furthermore suggest that FK506, unlike the action of this drug in model organisms, exerts its antiproliferative activity in a FKBP35-independent manner and, using cellular thermal shift assays, we identify putative FK506-targets beyond FKBP35. In addition to revealing first insights into the function of FKBP35, our results show that FKBP-binding drugs can adopt non-canonical modes of action - with major implications for the development of FK506-derived molecules active against parasites and other eukaryotic pathogens.
Topics: Humans; Antimalarials; Tacrolimus; Anti-Bacterial Agents; Drug Delivery Systems; Homeostasis; Malaria, Falciparum; Tacrolimus Binding Proteins
PubMed: 37934560
DOI: 10.7554/eLife.86975 -
European Journal of Medicinal Chemistry Dec 2023Parasitic diseases still pose a serious threat to human and animal health, particularly for millions of people and their livelihoods in low-income countries. Therefore,... (Review)
Review
Parasitic diseases still pose a serious threat to human and animal health, particularly for millions of people and their livelihoods in low-income countries. Therefore, research into the development of effective antiparasitic drugs remains a priority. Ivermectin, a sixteen-membered macrocyclic lactone, exhibits a broad spectrum of antiparasitic activities, which, combined with its low toxicity, has allowed the drug to be widely used in the treatment of parasitic diseases affecting humans and animals. In addition to its licensed use against river blindness and strongyloidiasis in humans, and against roundworm and arthropod infestations in animals, ivermectin is also used "off-label" to treat many other worm-related parasitic diseases, particularly in domestic animals. In addition, several experimental studies indicate that ivermectin displays also potent activity against viruses, bacteria, protozoans, trematodes, and insects. This review article summarizes the last 40 years of research on the antiparasitic effects of ivermectin, and the use of the drug in the treatment of parasitic diseases in humans and animals.
Topics: Animals; Humans; Antiparasitic Agents; Ivermectin; Parasitic Diseases
PubMed: 37793327
DOI: 10.1016/j.ejmech.2023.115838 -
Nature Communications May 2024Pentamidine and melarsoprol are primary drugs used to treat the lethal human sleeping sickness caused by the parasite Trypanosoma brucei. Cross-resistance to these two...
Pentamidine and melarsoprol are primary drugs used to treat the lethal human sleeping sickness caused by the parasite Trypanosoma brucei. Cross-resistance to these two drugs has recently been linked to aquaglyceroporin 2 of the trypanosome (TbAQP2). TbAQP2 is the first member of the aquaporin family described as capable of drug transport; however, the underlying mechanism remains unclear. Here, we present cryo-electron microscopy structures of TbAQP2 bound to pentamidine or melarsoprol. Our structural studies, together with the molecular dynamic simulations, reveal the mechanisms shaping substrate specificity and drug permeation. Multiple amino acids in TbAQP2, near the extracellular entrance and inside the pore, create an expanded conducting tunnel, sterically and energetically allowing the permeation of pentamidine and melarsoprol. Our study elucidates the mechanism of drug transport by TbAQP2, providing valuable insights to inform the design of drugs against trypanosomiasis.
Topics: Trypanosoma brucei brucei; Aquaglyceroporins; Cryoelectron Microscopy; Molecular Dynamics Simulation; Melarsoprol; Pentamidine; Biological Transport; Trypanocidal Agents; Protozoan Proteins; Humans
PubMed: 38734677
DOI: 10.1038/s41467-024-48445-4 -
The Lancet. Microbe Dec 2023Efficacy of sulfadoxine-pyrimethamine, the malaria chemoprophylaxis used in pregnant women, and in children when combined with amodiaquine, is threatened by the...
BACKGROUND
Efficacy of sulfadoxine-pyrimethamine, the malaria chemoprophylaxis used in pregnant women, and in children when combined with amodiaquine, is threatened by the accumulation of mutations in the Plasmodium falciparum dihydropteroate synthase (pfdhps) and dihydrofolate reductase (pfdhfr) genes. Data on the prevalence of resistant alleles in central Africa and the new pfdhps I431V mutation, particularly associated with other mutations to form the pfdhps vagKgs allele, are scarce. We explored the frequency and geographical distribution of pfdhps and pfdhfr mutations in central Africa in 2014-18, and assessed the evolutionary origin of the vagKgs allele.
METHODS
Samples were collected at 18 health-care centres in seven countries (Angola, Cameroon, Central African Republic, Democratic Republic of the Congo, Gabon, Nigeria, and Republic of the Congo) from patients who showed possible symptoms of malaria between March 1, 2014, and Oct 31, 2018. Samples that were positive for P falciparum were transported to a laboratory in Toulouse, France, and genotyped. The frequency of pfdhfr and pfdhps mutations was studied in 1749 samples. Microsatellites in pfdhps flanking regions and whole-genome analysis compared with parasite genomes from the data-sharing network MalariaGEN were performed on samples carrying the vagKgs allele.
FINDINGS
Mapping of the prevalence of single nucleotide polymorphisms and corresponding alleles of pfdhfr and pfdhps showed a substantial spread of alleles associated with sulfadoxine-pyrimethamine resistance in central Africa during the 2014-18 period, especially an increase going west to east in pfdhps alleles carrying the K540E and A581G mutations. A high prevalence of the pfdhps I431V mutation was observed in Cameroon (exceeding 50% in the northern region) and Nigeria. Genomic analysis showed a recent African emergence and a clonal expansion of the most frequent pfdhps vagKgs allele.
INTERPRETATION
Reduced sulfadoxine-pyrimethamine efficacy due to increased resistance is a worrying situation, especially because the malaria transmission level is high in central Africa. Although the resistance phenotype remains to be confirmed, the emergence and spread of the vagKgs allele in west and central Africa could challenge the use of sulfadoxine-pyrimethamine.
FUNDING
Toulouse Institute for Infectious and Inflammatory Diseases.
Topics: Child; Humans; Female; Pregnancy; Plasmodium falciparum; Cross-Sectional Studies; Antimalarials; Drug Resistance; Malaria, Falciparum; Mutation; Africa, Central; Dihydropteroate Synthase
PubMed: 37865113
DOI: 10.1016/S2666-5247(23)00211-2 -
PLoS Neglected Tropical Diseases Aug 2023In endemic foci, the use of an aquaphilic cream containing paromomycin with/without gentamicin to treat cutaneous leishmaniasis (CL) is safe, painless and cures 78-82%...
BACKGROUND
In endemic foci, the use of an aquaphilic cream containing paromomycin with/without gentamicin to treat cutaneous leishmaniasis (CL) is safe, painless and cures 78-82% of patients with New and Old World CL. Self-application in travelers requires evaluation.
METHODS
Travelers with 1-10 lesions of confirmed CL were prospectively treated with the paromomycin-gentamicin formulation (WR279396, 2012-2017, Group 1) and carefully follow up, or treated with a locally produced paromomycin-only cream (2018-2022, Group 2). The cream was applied once under supervision, then self-applied daily for 20-30 days. A cured lesion was defined as 100% re-epithelialization at day 42 without relapse at three months.
RESULTS
Medical features were similar in Group 1 (17 patients), and Group 2 (23 patients). Patients were infected with either Leishmania major, L. infantum, L. killicki, L. guyanensis, L. braziliensis, or L. naiffi. Intention-to-treat and per-protocol cure rates were 82% (95% confidence interval (CI) [64.23;100.00]) and 87% (95% CI [71,29;100.00]) in Group 1, and 69% (95% CI [50.76; 88.37]) and 76% (95% CI [57.97; 94.41]) in Group 2. In the pooled Group 1&2, 75% (95% CI [61.58;88.42]) (30/40) and 81% (95% CI [68,46;93.6]) (30/37) of patients were cured in intention-to-treat and per-protocol, respectively. There were no significant differences observed in the success rates between Old World and New World CL (83.3% vs. 60%, p = 0.14). Prospective observations in Group 1 showed that adverse events were mainly pruritus (24%) and pain (18%) on lesions (all mild or moderate). No mucosal involvement was observed in either group.
DISCUSSION
In this representative population of travelers who acquired CL either in the Old or New World, the 81% per-protocol cure rate of a self-applied aminoglycoside cream was similar to that observed in clinical trials.
Topics: Humans; Paromomycin; Antiprotozoal Agents; Prospective Studies; Leishmaniasis, Cutaneous; Aminoglycosides; Anti-Bacterial Agents; Gentamicins
PubMed: 37561802
DOI: 10.1371/journal.pntd.0011492 -
International Maritime Health 2024Schistosomiasis, caused by Schistosoma trematode worms, represents a significant global health challenge. This review offers a thorough examination of the disease's... (Review)
Review
Schistosomiasis, caused by Schistosoma trematode worms, represents a significant global health challenge. This review offers a thorough examination of the disease's epidemiology, transmission dynamics, diagnostic modalities, and treatment options. Diagnostic techniques encompass direct parasitological methods, immunological assays, DNA/RNA detection, and biomarker utilization, each with distinct advantages and limitations. There is an urgent need for improved diagnostic tools with enhanced sensitivity and specificity. Praziquantel remains the cornerstone of treatment, exhibiting efficacy against all Schistosoma species, while the potential of artemisin derivatives in combination therapy is also explored. In this review, we focus on the importance of praziquantel administration as the central aspect of schistosomiasis treatment, highlighting ongoing efforts to optimize its utilization for improved patient outcomes.
Topics: Praziquantel; Humans; Schistosomiasis; Anthelmintics; Animals; Schistosoma
PubMed: 38647059
DOI: 10.5603/imh.99453 -
Nature Communications Oct 2023Post-infectious conditions present major health burdens but remain poorly understood. In Chagas disease (CD), caused by Trypanosoma cruzi parasites, antiparasitic agents...
Post-infectious conditions present major health burdens but remain poorly understood. In Chagas disease (CD), caused by Trypanosoma cruzi parasites, antiparasitic agents that successfully clear T. cruzi do not always improve clinical outcomes. In this study, we reveal differential small molecule trajectories between cardiac regions during chronic T. cruzi infection, matching with characteristic CD apical aneurysm sites. Incomplete, region-specific, cardiac small molecule restoration is observed in animals treated with the antiparasitic benznidazole. In contrast, superior restoration of the cardiac small molecule profile is observed for a combination treatment of reduced-dose benznidazole plus an immunotherapy, even with less parasite burden reduction. Overall, these results reveal molecular mechanisms of CD treatment based on simultaneous effects on the pathogen and on host small molecule responses, and expand our understanding of clinical treatment failure in CD. This link between infection and subsequent persistent small molecule perturbation broadens our understanding of infectious disease sequelae.
Topics: Animals; Trypanocidal Agents; Chagas Disease; Nitroimidazoles; Heart; Trypanosoma cruzi; Disease Progression
PubMed: 37880260
DOI: 10.1038/s41467-023-42247-w -
Frontiers in Cellular and Infection... 2023
Topics: Antimalarials; Insecticide Resistance
PubMed: 37719669
DOI: 10.3389/fcimb.2023.1274741 -
Trends in Parasitology Dec 2023The World Health Organization (WHO) recently proposed a new operational definition which designates communities with ≥10% prevalence of Schistosoma spp. infection as a... (Review)
Review
The World Health Organization (WHO) recently proposed a new operational definition which designates communities with ≥10% prevalence of Schistosoma spp. infection as a persistent hotspot, when, after at least two rounds of high-coverage annual preventive chemotherapy, there is a lack of appropriate reduction. However, inconsistencies and challenges from both biological and operational perspectives remain, making the prescriptive use of this definition difficult. Here, we present a comprehensive analysis of the use of the term 'hotspot' across schistosomiasis research over time, including both literature searches and opinions from a range of stakeholders, to assess the utility and generalisability of the new WHO definition of a persistent hotspot. Importantly, we propose an updated definition based on our analyses.
Topics: Animals; Praziquantel; Anthelmintics; Schistosoma haematobium; Schistosomiasis; Schistosoma mansoni
PubMed: 37806786
DOI: 10.1016/j.pt.2023.09.006