Computational repurposing of benzimidazole anthelmintic drugs as potential colchicine binding site inhibitors

Background: Although some benzimidazole-based anthelmintic drugs are found to possess anticancer activity, their modes of binding interactions have not been reported. Methodology: In this study, we aimed to investigate the binding interactions and electronic configurations of nine benzimidazole-based anthelmintics against one of the well-known cancer targets (tubulin protein). Results: Binding affinities of docked benzimidazole drugs into colchicine-binding site were calculated where flubendazole > oxfendazole > nocodazole > mebendazole. Flubendazole was found to bind more efficiently with tubulin protein than other drugs. Quantum mechanics studies revealed that the electron density of HOMO of flubendazole and mebendazole together with their molecular electrostatic potential map are closely similar to that of nocodazole. Conclusion: Our study has ramifications for considering repurposing of flubendazole as a promising anticancer candidate.

Loss of the central rachis and synaptonemal complexes during meiotic prophase in female Ascaris lumbricoides var. suum after exposure to albendazole

Albendazole, a benzimidazole anthelmintic, interferes with the formation of microtubules and inhibits meiosis in the nematode Ascaris lumbricoides var. suum. Pigs treated with albendazole had worms in their uteri that had a severely deteriorated central rachis, complete loss of synaptonemal complexes and irregular oocytes at meiotic prophase I. The nuclear matrix and envelope were poorly formed and there was formation of accessory nuclei. This study represents the first examination of the changes in meiotic nuclear architecture and meiotic chromosomes after exposure to albendazole. These results provide the basis for the loss of fecundity in A. suum after exposure to albendazole resulting in control in the population of the parasitic nematode.

Pharmacokinetics, Safety, and Tolerability of Oxfendazole in Healthy Adults in an Open-Label Phase 1 Multiple Ascending Dose and Food Effect Study

ABSTRACT Neurocysticercosis and trichuriasis are difficult-to-treat parasitic infections that affect more than 1.5 billion people worldwide. Oxfendazole, a potent broad-spectrum benzimidazole anthelmintic approved for use in veterinary medicine, has shown substantial antiparasitic activity against neurocysticercosis and intestinal helminths in preclinical studies. As part of a program to transition oxfendazole from veterinary medicine to human use, phase I multiple ascending dose and food effect studies were conducted. Thirty-six healthy adults were enrolled in an open-label study which evaluated (i) the pharmacokinetics and safety of oxfendazole following multiple ascending doses of oxfendazole oral suspension at 3, 7.5, and 15 mg/kg once daily for 5 days and (ii) the effect of food on oxfendazole pharmacokinetics and safety after a single 3-mg/kg dose administered following an overnight fast or the consumption of a fatty breakfast. Following multiple oral dose administration, the intestinal absorption of oxfendazole was rapid, with the time to maximum concentration of drug in serum (Tmax) ranging from 1.92 to 2.56 h. A similar half-life of oxfendazole (9.21 to 11.8 h) was observed across all dose groups evaluated, and oxfendazole exhibited significantly less than a dose-proportional increase in exposure. Oxfendazole plasma exposures were higher in female subjects than in male subjects. Following daily administration, oxfendazole reached a steady state in plasma on study day 3, with minimal accumulation. Food delayed the oxfendazole Tmax by a median of 6.88 h and resulted in a 49.2% increase in the maximum observed drug concentration in plasma (Cmax) and an 86.4% increase in the area under the concentration-time curve (AUC). Oxfendazole was well tolerated in all study groups, and there were no major safety signals identified in this study. (This study has been registered at ClinicalTrials.gov under identifier NCT03035760.)

Albendazole-Induced SIRT3 Upregulation Protects Human Leukemia K562 Cells from the Cytotoxicity of MCL1 Suppression

Previous studies have shown that MCL1 stabilization confers cancer cells resistance to microtubule targeting agents (MTAs) and functionally extends the lifespan of MTA-triggered mitotically arrested cells. Albendazole (ABZ), a benzimidazole anthelmintic, shows microtubule-destabilizing activity and has been repositioned for cancer therapies. To clarify the role of MCL1 in ABZ-induced apoptosis, we investigated the cytotoxicity of ABZ on human leukemia K562 cells. Treatment with ABZ for 24 h did not appreciably induce apoptosis or mitochondrial depolarization in K562 cells, though it caused the mitotic arrest of K562 cells. ABZ-evoked p38 MAPK activation concurrently suppressed Sp1-mediated MCL1 expression and increased SIRT3 mRNA stability and protein expression. ABZ and A-1210477 (an MCL1 inhibitor) enhanced the cytotoxicity of ABT-263 (a BCL2/BCL2L1 inhibitor) to their effect on MCL1 suppression. Unlike ABZ, A-1210477 did not affect SIRT3 expression and reduced the survival of K562 cells. Overexpression of SIRT3 attenuated the A-1210477 cytotoxicity on K562 cells. ABZ treatment elicited marked apoptosis and ΔΨm loss in ABT-263-resistant K562 (K562/R) cells, but did not alter SIRT3 expression. Ectopic expression of SIRT3 alleviated the cytotoxicity of ABZ on K562/R cells. Collectively, our data demonstrate that ABZ-induced SIRT3 upregulation delays the apoptosis-inducing effect of MCL1 suppression on apoptosis induction in K562 cells.

The global diversity of Haemonchus contortus is shaped by human intervention and climate

Haemonchus contortus is a haematophagous parasitic nematode of veterinary interest. We have performed a survey of its genome-wide diversity using single-worm whole genome sequencing of 223 individuals sampled from 19 isolates spanning five continents. We find an African origin for the species, together with evidence for parasites spreading during the transatlantic slave trade and colonisation of Australia. Strong selective sweeps surrounding the β-tubulin locus, a target of benzimidazole anthelmintic drug, are identified in independent populations. These sweeps are further supported by signals of diversifying selection enriched in genes involved in response to drugs and other anthelmintic-associated biological functions. We also identify some candidate genes that may play a role in ivermectin resistance. Finally, genetic signatures of climate-driven adaptation are described, revealing a gene acting as an epigenetic regulator and components of the dauer pathway. These results begin to define genetic adaptation to climate in a parasitic nematode.

The global diversity of the major parasitic nematodeHaemonchus contortusis shaped by human intervention and climate

The gastrointestinal parasiteHaemonchus contortusis an haematophagous parasitic nematode of veterinary interest and a model for the study of drug resistance mechanisms or host-parasite interactions. To understand its evolutionary history, and its ability to adapt in the face of climatic and drug pressure, we have performed an extensive survey of genome-wide diversity using single-worm whole genome sequencing of 223 individuals sampled from 19 isolates spanning five continents. The pattern of global diversity is driven by an African origin for the species, together with contemporary dispersal that is consistent with modern human movement, with evidence for parasites spreading during the transatlantic slave trade and colonisation of Australia presented. Strong selective sweeps were identified in independent populations each surrounding the β-tubulin locus, a target of benzimidazole anthelmintic drug treatment used widely to controlH. contortusinfections. These signatures of selection were further supported by signals of diversifying selection enriched in genes involved in response to drugs, as well as other anthelmintic-associated biological functions including pharyngeal pumping and oviposition. From these analyses, we identify some known, and previously undescribed, candidate genes that may play a role in ivermectin resistance. Finally, we describe genetic signatures of climate-driven adaptation, revealing a gene acting as an epigenetic regulator and components of thedauerpathway may play a role in adaptation in the face of climatic fluctuations. These results begin to define genetic adaptation to climate for the first time in a parasitic nematode, and provides insight into the ongoing expansion in the range ofHaemonchus contortus, which may have consequences for the management of this parasite.

Anthelmintic resistance to cattle gastrointestinal nematodes in selected dairy farms of Mymensingh and Sirajganj districts of Bangladesh

Correction: Table 1 and Table 2 have were omitted from the PDF in error. They were added to page 89 on 17th May 2018.Anthelmintic resistance (AR) to commonly used dewormers is one of the major world-wide constrain in livestock production. The present study was investigated the status of AR in BAU dairy farm, Mymensingh and Talukder dairy farm, Sirajganj. Faecal egg count reduction test (FECRT) was applied to assess AR in cattle of two dairy farms during January to June 2017. The anthelmintics tested were Albendazole (ABZ), a benzimidazole anthelmintic (Almex®, Square Ltd.) and Ivermectin (IVM) (Vermic®, Techno drugs Ltd.), administered at the doses recommended by the manufacturers. In each farm, cattle were divided into treatment and control (not treated) group based on faecal egg counts (FEC), that is at least 200 eggs/g. At 14 days after treatment, faecal samples were collected for post-treatment FEC, which is compared between treatment and control group. Resistance was defined if there was <95% reduction, with lower 95% confidence limit (CL) <90% in the FEC. AR was present in both the dairy farms involved in this study. The FECRT using ABZ revealed 79.7% (95% CL 87.9, 65.8) reduction and 95.8% (95% CL 98.7, 87.1) reduction of FEC in BAU and Talukder dairy farms, respectively. Also, FECRT using IVM revealed 77.9% (95% CL 97.7, 85.5) and 94.2% (95% CL 97.7, 85.5) reduction of FEC in BAU and Talukder dairy farms, respectively. Our study suggest that AR is present in both selected dairy farms and further extensive studies are required to determine the extent of AR in different cattle farms of Bangladesh.Res. Agric., Livest. Fish.5(1): 87-92, April 2018