Search Results (31)

The treatment of parasitic infections has evolved in terms of effectiveness and the prevention of drug resistance. This is highlighted by the discovery of ivermectin (IVM), a macrocyclic lactone and broad-spectrum antiparasitic agent. IVM garnered scientific attention by presenting a therapeutic alternative in the field of veterinary medicine due to its control of multiple parasite species, including nematodes and soil-transmitted helminths. Shortly after its discovery, IVM was approved for human use by the World Health Organization (WHO) and United States Food and Drug Administration (FDA) for combating head lice, onchocerciasis, rosacea, scabies, and worm infestations within the gastrointestinal tract (GIT). In veterinary medicine, IVM is available in a range of formulations and can be administered via different routes (i.e., oral, topical, and parenteral), whereas for humans, IVM is only approved as a single oral dose and dermal cream. Establishing a comprehensive overview of IVM’s applications in both human and veterinary medicine is necessary, particularly in light of its repurposing potential as a treatment for various conditions and emerging diseases. Given its primary application in veterinary medicine, there is a need to enhance the development of dosage forms suitable for human use. Therefore, this review details the discovery, mechanisms, and applications of IVM, while also examining the challenges of resistance, side-effects, and controversy surrounding its use, to ultimately emphasize the importance of targeted, optimized IVM delivery via tailored dosage form development in animals and humans as part of the One Health approach to interlink innovations across veterinary and human medicine fields. Full article

The filarioid nematode Dirofilaria immitis is the causative agent of heartworm disease, a major parasitic infection of canids, felids and occasionally humans. Current prevention relies on macrocyclic lactone-based chemoprophylaxis, but the emergence of drug resistance highlights the need for new intervention strategies. Here, we applied a machine learning (ML)-based framework to predict and prioritise essential genes in D. immitis in silico, using genomic, transcriptomic and functional datasets from the model organisms Caenorhabditis elegans and Drosophila melanogaster. With a curated set of 26 predictive features, we trained and evaluated multiple ML models and, using a defined threshold, we predicted 406 ‘high-priority’ essential genes. These genes showed strong transcriptional activity across developmental stages and were inferred to be enriched in pathways related to ribosome biogenesis, translation, RNA processing and signalling, underscoring their potential as anthelmintic targets. Transcriptomic analyses suggested that these genes are associated with key reproductive and neural tissues, while chromosomal mapping revealed a relatively even genomic distribution, in contrast to patterns observed in C. elegans and Dr. melanogaster. In addition, initial evidence suggested structural variation in the X chromosome compared with a recently published D. immitis assembly, indicating the importance of integrating long-read sequencing with high-throughput chromosome conformation capture (Hi-C) mapping. Overall, this study reinforces the potential of ML-guided approaches for essential gene discovery in parasitic nematodes and provides a foundation for downstream validation and therapeutic target development. Full article

Resistance to anthelmintics in gastrointestinal nematodes (GINs) is highly prevalent, as these parasites have been treated with anthelmintics for decades in ruminants and horses. Anthelmintics belong to different classes, each with a different mode of action. The most used are benzimidazoles and macrocyclic lactones and, to a lesser extent, levamisole and pyrantel in herbivores, as estimated from the literature. Combining these classes should be effective in controlling GIN. However, several farmers’ practices tend to promote GIN resistance. Therefore, it is unclear whether the use of anthelmintic associations is a sustainable solution for controlling resistance in natural conditions. It is not easy to establish the association of anthelmintic resistances on farms since rarely several anthelmintics and their combinations are used on a single farm. Composed probability calculations were employed when literature data indicated the presence of resistance (to benzimidazoles, levamisole, or macrocyclic lactones) in several ruminant GIN cases. The efficacy of different anthelmintics (benzimidazoles, pyrantel, or macrocyclic lactones) was evaluated in terms of the correlation between faecal nematode egg counts in horses in the available literature. No associations of anthelmintic resistance were found between the different classes of anthelmintics in either ruminants or horses. However, the association between anthelmintic resistance in GIN may appear in the long term. It is presumed that combining drugs may reduce the development of resistance and allow better control of infection on farms where resistance is already established to a low level. Full article

Anthelmintic resistance (AR) in gastrointestinal nematodes is a growing global concern that threatens effective parasite control in livestock farming. This study aimed to assess gastrointestinal nematode (GIN) control practices and identify risk factors associated with AR development on Lithuanian sheep farms. A cross-sectional survey was conducted between 2022 and 2023 among 71 members of the Lithuanian Sheep Breeders Association, covering farm management, grazing, and deworming practices. Anthelmintics were used by 90.2% of farmers, with most treating their flocks twice a year. Only 18.3% of farmers performed parasitological testing to guide treatments, with significantly more organic farms applying this approach than traditional farms. Treatment frequencies were significantly higher in traditional farms. Most farmers (45.1%) relied on the visual appraisal of sheep weight for dosing, while 35.2% dosed according to the weight of a medium-sized animal. Macrocyclic lactones were the most commonly used anthelmintics (50.7%). Quarantine procedures for new animals were implemented by less than half of the farmers (44.4%), while others treated without isolation (56.6%). These findings indicate reliance on non-strategic parasite control methods and limited use of diagnostics, highlighting the need for improved farmer education to promote sustainable parasite control and reduce AR risk in Lithuanian sheep farms. Full article

New intervention methods and product formulations are needed to better control pyrethroid-resistant Aedes aegypti populations and mitigate the risk of mosquito-borne disease. ReMoa Tri is a novel adulticidal space spray that utilizes a different mode of action than the commonly used adulticides: pyrethroids and organophosphates. As a triple-action space spray, ReMoa Tri combines three components: Fenpropathrin, a mixed-type I/II pyrethroid; abamectin, a macrocyclic lactone; and C8910, a patented fatty acid chain. Prior studies performed by Collier Mosquito Control District showed that ReMoa Tri is effective at controlling type I pyrethroid-resistant Ae. aegypti mosquitoes. To further validate these results and the performance of ReMoa Tri, we conducted a semi-field evaluation using ground and aerial ULV (ultra-low volume) applications with field-caught deltamethrin-resistant Ae. aegypti and a susceptible Ae. aegypti laboratory strain. Ground evaluations tested ReMoa Tri and a type II pyrethroid-based product, DeltaGard. While ReMoa Tri was equally effective against Collier’s deltamethrin-resistant Ae. aegypti and the susceptible laboratory strain, DeltaGard was effective against both strains, with reduced efficacy at farther distances. Similarly, aerial evaluations also showed that ReMoa Tri was equally effective against Collier’s deltamethrin-resistant Ae. aegypti strain and susceptible laboratory strain. This study further confirms ReMoa Tri’s potential as an effective alternative to pyrethroid-based adulticides, both in ground and aerial applications, for managing pyrethroid-resistant Ae. aegypti. Full article

Signal-dependent transport into and out of the nucleus mediated by members of the importin (IMP) superfamily is crucial for eukaryotic function, with inhibitors targeting IMPα being of key interest as anti-infectious agents, including against the apicomplexan Plasmodium species and Toxoplasma gondii, causative agents of malaria and toxoplasmosis, respectively. We recently showed that the FDA-approved macrocyclic lactone ivermectin, as well as several other different small molecule inhibitors, can specifically bind to and inhibit P. falciparum and T. gondii IMPα functions, as well as limit parasite growth. Here we focus on the FDA-approved antiparasitic moxidectin, a structural analogue of ivermectin, for its IMPα-targeting and anti-apicomplexan properties for the first time. We use circular dichroism and intrinsic tryptophan fluorescence measurements to show that moxidectin can bind directly to apicomplexan IMPαs, thereby inhibiting their key binding functions at low μM concentrations, as well as possessing anti-parasitic activity against P. falciparum in culture. The results imply a class effect in terms of IMPα’s ability to be targeted by macrocyclic lactone compounds. Importantly, in the face of rising global emergence of resistance to approved anti-parasitic agents, the findings highlight the potential of moxidectin and possibly other macrocyclic lactone compounds as antimalarial agents. Full article

The widespread and uncontrolled use of anthelmintic products has contributed to the emergence of anthelmintic resistance (AR). This phenomenon globally threatens the productivity and welfare of small ruminants. A questionnaire consisting of 34 questions was handed to 234 goat farmers across Romania to gain insight into control practices against internal parasites and the farmers’ perception of the parasitic infections present in their herds and the efficacy of anthelmintic treatments. The majority of farmers (88.5%) admitted they had never submitted fecal samples for parasitological laboratory analysis, and 77.4% had treated the animals on their own. In general, the farmers dewormed their goats based on visual body weight estimation. Prophylactic anthelmintic treatment was practiced by more than 85% of the farmers. A traditional control approach based on treating the entire herd at fixed time intervals is widespread among Romanian goat and sheep farmers. The most commonly used anthelmintic drugs in the previous 3 years (2021–2023) were benzimidazoles (85.5%) and macrocyclic lactones (81.6%). Poor anthelmintic efficacy was suspected by 14.5% of farmers, and the minority (18.0%) considered internal parasites as a problem in their herds. Regarding the farmers’ perception of the presence of parasites, there was a significant level of uncertainty. This is the first survey carried out in Romanian goat herds, and it provides up-to-date information on practices aimed at controlling internal parasites. Full article

Anthelmintic resistance in small ruminants is a serious worldwide problem. To reduce their spread, it is essential to know the prevalence of helminths on farms and the control practices adopted. As these studies in the Calabria region of southern Italy are fragmentary and outdated, a study on the prevalence of helminths in small ruminant holdings in this area has been conducted. The measures implemented to control helminths were also evaluated through questionnaires administered to farmers. In particular, on 90 farms (45 sheep and 45 goats), 1800 faecal samples from 900 sheep and 900 goats were collected in the spring. Using the FLOTAC dual technique, parasitological examinations demonstrated the presence of gastrointestinal nematodes in 100% of sheep and goat farms, followed by Nematodirus spp. (84.44% sheep and 48.89% goats), Moniezia spp. (73.33% sheep and 35.56% goats), Trichuris ovis (48.89% sheep and 42.22% goats), lungworms (28.89% sheep and 42.22% goats), Strongyloides papillosus (40% sheep and 26.67% goats), Dicrocoelium dendriticum (13.33% sheep and 26.67% goats), Calicophoron daubneyi (6.67% sheep and 31.11% goats), Fasciola hepatica (6.67% sheep and 4.44% goats), and Skrjabinema ovis (4.44% sheep and goats). The questionnaires showed that 82% and 85% of the farmers had applied pasture rotation, and that 93.3% and 86.6% had used anthelmintics in the previous year for sheep and goats, respectively. Only 24.4% of sheep farmers and 11.3% of goat farmers had carried out parasitological tests prior to treatments. The most used classes of anthelmintics were macrocyclic lactones and benzimidazoles, and only in 21.6% and 15.6%, for sheep and goats, respectively, was drug rotation carried out. These results denote that helminths represent a health problem for small ruminants and highlight a lack of knowledge of parasite control strategies among farmers. In these conditions, anthelmintic resistance phenomena could develop over time. Therefore, it is necessary to implement all possible strategies for the control of helminths, and to prevent the spread of anthelmintic resistance phenomena on farms in southern Italy. Full article

Tuberculosis is one of the most common infectious diseases in the world, caused by Mycobacterium tuberculosis. The outbreak of multiple drug-resistant tuberculosis has become a major challenge to prevent this disease worldwide. ClpC1 is a Clp ATPase protein of Mycobacterium tuberculosis, functioning as a chaperon when combined with the Clp complex. ClpC1 has emerged as a new target to discover anti-tuberculosis drugs. This study aimed to explore the ClpC1 inhibitors from actinomycetes, which have been known to provide abundant sources of antibiotics. Two cyclic peptides, including nocardamin (1), halolitoralin A (3), and a lactone pleurone (2), were isolated from the culture of Streptomyces aureus (VTCC43181). The structures of these compounds were determined based on the detailed analysis of their spectral data and comparison with references. This is the first time these compounds have been isolated from S. aureus. Compounds 1–3 were evaluated for their affection of ATPase activity of the recombinant ClpC1 protein. Of these compounds, halolitoralin A (1), a macrocyclic peptide, was effective for the ATPase hydrolysis of the ClpC1 protein. Full article

The emergence of multidrug-resistant strains requires the urgent discovery of new antibacterial drugs. In this context, an antibacterial screening of a subset of anthelmintic avermectins against gram-positive and gram-negative strains was performed. Selamectin completely inhibited bacterial growth at 6.3 μg/mL concentrations against reference gram-positive strains, while no antibacterial activity was found against gram-negative strains up to the highest concentration tested of 50 μg/mL. Given its relevance as a community and hospital pathogen, further studies have been performed on selamectin activity against Staphylococcus aureus (S. aureus), using clinical isolates with different antibiotic resistance profiles and a reference biofilm-producing strain. Antibacterial studies have been extensive on clinical S. aureus isolates with different antibiotic resistance profiles. Mean MIC₉₀ values of 6.2 μg/mL were reported for all tested S. aureus strains, except for the macrolide-resistant isolate with constitutive macrolide-lincosamide-streptogramin B resistance phenotype (MIC₉₀ 9.9 μg/mL). Scanning Electron Microscopy (SEM) showed that selamectin exposure caused relevant cell surface alterations. A synergistic effect was observed between ampicillin and selamectin, dictated by an FIC value of 0.5 against methicillin-resistant strain. Drug administration at MIC concentration reduced the intracellular bacterial load by 81.3%. The effect on preformed biofilm was investigated via crystal violet and confocal laser scanning microscopy. Selamectin reduced the biofilm biomass in a dose-dependent manner with minimal biofilm eradication concentrations inducing a 50% eradication (MBEC₅₀) at 5.89 μg/mL. The cytotoxic tests indicated that selamectin exhibited no relevant hemolytic and cytotoxic activity at active concentrations. These data suggest that selamectin may represent a timely and promising macrocyclic lactone for the treatment of S. aureus infections. Full article

Helminth parasitic infections are a considerable constraint to the livestock industries worldwide. Nematode parasites cause the major proportion of harm to livestock. The infections caused are accountable for severe economic losses in cattle, goat and sheep farming industries. Morbidity and mortality in livestock due to parasitic diseases are increasing alarmingly. Also, their zoonotic influence on human health is considered significant. Anthelmintic drugs have been developed occasionally to curb this disease and prevent major losses. But the development of resistance against these drugs has put another constraint on this flourishing industry. Helminth parasites have developed resistance against three main classes of anthelmintics: benzimidazoles, macrocyclic lactones and nicotinic agonists. With the intensification of resistance, various screening and confirmatory tests have been developed for the speedy introduction of newer drugs in the livestock industry. At the same time, designing and launching novel anthelmintics is time-consuming and economically restrained. Phytochemicals attract much attention because of their pharmacotherapeutic potential, least toxic profile and low environmental hazards. A lot of work is going on plant-based anthelmintic drugs throughout the world. Plants possessing anthelmintic activity have been found efficacious against gastrointestinal parasites. Nevertheless, these herbal medicines have various drawbacks, which include poor efficacy and the absence of target selectivity. These problems are now being taken care of with the help of nanotechnology. Nanoparticles improve the drug’s effectiveness, enhance drug delivery, and target selectivity at specific sites. A comprehensive literature survey was carried out via electronic searches of Google Scholar, PubMed, MEDLINE, Science Direct, Scopus and Cochrane Library databases and based on inclusion and exclusion criteria; articles were selected for this review. The review aims at providing a comprehensive overview of plant-based nanoparticles as therapeutic alternatives over conventional synthetic anthelmintic drugs. It also encompasses the methods of detection of resistance and the ways to overcome this menace. The effectiveness of various organic and inorganic nanoparticles against helminthes is also discussed in this review. Full article

Dirofilaria immitis is a parasitic nematode and causes dirofilariosis, a potentially fatal pulmonary infection which primarily infects canids. Dirofilariosis infections are controlled via prophylactic macrocyclic lactone (ML) regimens. Recent evidence has confirmed the development of ML-resistant isolates in the USA, which are genetically distinct from wildtype populations. Single nucleotide polymorphisms (SNP) associated with ML-resistant phenotypes were clinically validated in USA populations. In this study, 3 USA laboratory-maintained isolates (Berkeley, Georgia II, and WildCat) and 11 randomly selected European clinical samples from 7 hosts were analyzed. The samples tested were fresh microfilaria (mf) in blood or adult worms preserved in ethanol. The samples underwent MiSeq sequencing of the top 9 SNP associated with ML resistance. The results provide the first genotypic analysis of the three USA laboratory-maintained isolates and any European samples. The European clinical samples show no genomic evidence of ML resistance based on the 9 SNP. The early adoption of genotyping of clinical D. immitis samples could provide an early indication of the potential development of ML resistance and aid to distinguish clinical cases of heartworm infection due to ML resistance from those due to a lack compliance with the recommended treatments, as has been seen in North America. Full article

The number of reported macrocyclic lactones (ML) resistance cases across all livestock hosts is steadily increasing. Different studies in the parasitic nematode Haemonchus contortus assume the participation of cytochrome P450s (Cyps) enzymes in ML resistance. Still, functional data about their individual contribution to resistance or substrate specificity is missing. Via microinjection, transgenic Caenorhabditis elegans expressing HCON_00141052 (transgene-Hco-cyp-13A11) from extrachromosomal arrays were generated. After 24 h of exposure to different concentrations of ivermectin (IVM), ivermectin aglycone (IVMa), selamectin (SEL), doramectin (DRM), eprinomectin (EPR), and moxidectin (MOX), motility assays were performed to determine the impact of the H. contortus Cyp to the susceptibility of the worms against each ML. While transgene-Hco-cyp-13A11 significantly decreased susceptibility to IVM (four-fold), IVMa (2-fold), and SEL (3-fold), a slight effect for DRM and no effect for MOX, and EPR was observed. This substrate specificity of Hco-cyp-13A11 could not be explained by molecular modeling and docking studies. Hco-Cyp-13A11 molecular models were obtained for alleles from isolates with different resistance statuses. Although 14 amino acid polymorphisms were detected, none was resistance specific. In conclusion, Hco-cyp-13A11 decreased IVM, IVMa, and SEL susceptibility to a different extent, but its potential impact on ML resistance is not driven by polymorphisms. Full article

Abamectin, produced by the soil-dwelling actinomycete Streptomyces avermitilis, belongs to the macrocyclic lactones class of pesticides, has nematocidal, acaricidal, and insecticidal activity, and is highly effective when used against targeted species. Bemisia tabaci, the tobacco whitefly, is a highly destructive insect to agricultural production worldwide, and various insecticide-resistant strains have been identified in China. Here, we monitored levels of resistance to abamectin in twelve field-collected B. tabaci populations from northern China, and confirmed that, compared with the lab reference strain, six field populations exhibited strong abamectin resistance, while the other six exhibited low-to-medium resistance. Among these, the Xinzheng (XZ) population displayed about a 40-fold increased resistance to abamectin, and experienced significant cross-resistance to chlorpyrifos and imidacloprid. The abamectin resistance of XZ was found to be autosomal and incompletely dominant. Metabolic enzyme and synergism tests were conducted, and two metabolic enzymes, glutathione S-transferase and P450 monooxygenase, were found to be conducive to the field-developed abamectin resistance of the XZ population. The above results provide valuable information that can be used in identifying new pest control strategies and delaying the evolution of resistance to abamectin in field populations of whiteflies. Full article

Dirofilaria immitis is a zoonotic parasitic nematode that infects domestic and wild canids, among its vertebrate hosts. The genetic analysis of D. immitis nowadays transcends the need for genetic taxonomy of nematodes, such as the study of resistance to macrocyclic lactone. We expanded the use of long-read nanopore-based sequencing technology on nematodes by performing genomic de novo assembly of a D. immitis specimen retrieved from a canine cardiopulmonary dirofilariasis case using the ONT MinION platform, followed by the study of macrocyclic lactone resistance. The assembled genome of D. immitis consists of 110 contigs with an N50 of 3687191. The genome size is 87899012 and contains a total of 9741 proteins; 6 ribosomal RNAs, with three belonging to the small subunit (18S) and three to the large subunit (28S); and 73 tRNAs. Subsequent analysis of six loci previously characterized as being associated to macrocyclic lactone resistance selection pressure showed that four have a genotype associated with either some loss of efficacy or the resistance phenotype. Considering the zoonotic potential of D. immitis, the identification of a resistant parasite alerts for the overuse of macrocyclic lactone in the region, which poses a potential risk to both veterinary and human public health. Full article