Papers by Jan Clyden B. Tenorio
Veterinary World, Dec 6, 2024
Background and Aim: Mutations in the β-tubulin genes of helminths confer benzimidazole (BZ) resis... more Background and Aim: Mutations in the β-tubulin genes of helminths confer benzimidazole (BZ) resistance by reducing the drug’s binding efficiency to the expressed protein. However, the effects of these resistance-associated mutations on tubulin dimer formation in soil-transmitted helminths remain unknown. Therefore, this study aimed to investigate the impact of these mutations on the in silico dimerization of hookworm α- and β-tubulins using open-source bioinformatics tools.
Materials and Methods: Using AlphaFold 3, the α- and β-tubulin amino acid sequences of Ancylostoma ceylanicum were used to predict the structural fold of the hookworm tubulin heterodimer. The modeled complexes were subjected to several protein structure quality assurance checks. The binding free energies, overall binding affinity, dissociation constant, and interacting amino acids of the complex were determined. The dimer’s structural flexibility and motion were simulated through molecular dynamics.
Results: BZ resistance-associated amino acid substitutions in the β-tubulin isotype 1 protein of hookworms altered tubulin dimerization. The E198K, E198V, and F200Y mutations conferred the strongest and most stable binding between the α and β subunits, surpassing that of the wild-type. In contrast, complexes with the Q134H and F200L mutations exhibited the opposite effect. Molecular dynamics simulations showed that wild-type and mutant tubulin dimers exhibited similar dynamic behavior, with slight deviations in those carrying the F200L and E198K mutations.
Conclusion: Resistance-associated mutations in hookworms impair BZ binding to β-tubulin and enhance tubulin dimer interactions, thereby increasing the parasite’s ability to withstand treatment. Conversely, other mutations weaken these interactions, potentially compromising hookworm viability. These findings offer novel insights into helminth tubulin dimerization and provide a valuable foundation for developing anthelmintics targeting this crucial biological process.
Keywords: Ancylostoma, anthelmintic resistance, microtubules, soil-transmitted helminths.
Frontiers in Veterinary Science, Nov 28, 2023
Animal Diseases, 2024
Zoonotic hookworm infections remain a significant public health problem, causing nearly 500 milli... more Zoonotic hookworm infections remain a significant public health problem, causing nearly 500 million cases globally and approximately four million disability-adjusted life years lost annually. More than one-fifth of these cases are attributed to Ancylostoma ceylanicum, an emerging zoonotic health issue in the Asia-Pacific region. This review presents key research gaps regarding the epidemiology, diagnosis, control, prevention and elimination of A. ceylanicum and other canine zoonotic hookworms as neglected health threats. A. ceylanicum is the second most prevalent human hookworm in the region; it is the most common hookworm among dogs and cats-reservoirs of zoonotic infections. Previous population genetic and phylogenetic analyses revealed that A. ceylanicum has three possible transmission dynamics: zoonotic, animal-only, and human-only pathways. The actual burden of zoonotic ancylostomiasis in most endemic countries remains unknown due to the use of parasitological techniques (e.g., Kato-Katz thick smear and floatation techniques) that have reduced diagnostic performance and do not allow accurate species identification in helminth surveys. The emergence of benzimidazole resistance in soil-transmitted helminths (STHs), including hookworms, is a concern due to the protracted implementation of mass drug administration (MDA). Resistance is conferred by single nucleotide polymorphisms (SNPs) that occur in the β-tubulin isotype 1 gene. These mutations have been reported in drug-resistant A. caninum but have not been found in A. ceylanicum in the field. A. ceylanicum remains understudied in the Asia-Pacific region. The zoonotic nature of the parasite warrants investigation of its occurrence in human and animal reservoir hosts to understand the dynamics of zoonotic transmission in different endemic foci. The detection of benzimidazole resistance-associated SNPs in zoonotic hookworms from Asia-Pacific countries has yet to be thoroughly explored. Considering the high level of hookworm endemicity in the region, the circulation of resistant isolates between humans and animals potentially presents a significant One Health threat that can undermine current MDA and proposed animal deworming-based control efforts.
Journal of livestock science, Feb 5, 2022
The accelerated pace at which human development has been set into has resulted into fast-tracking... more The accelerated pace at which human development has been set into has resulted into fast-tracking the emergence of novel diseases that affect both humans and animals. One of these is the emergence of infectious zoonotic diseases that have threatened human health since time immemorial. The emergence of Highly Pathogenic Avian Influenza (HPAI) H5:N1 from poultry in 2002, Severe acute respiratory syndrome coronavirus (SARS-CoV) from civets and bats in 2003, Middle East Respiratory Syndrome coronaviruses (MERS-CoV) from camelids in 2014, and most recently in SARS-CoV 2 or COVID-19, which reportedly came from bats, should serve as lessons that should be taken seriously. Factors that have resulted in the emergence of these illnesses include, but are not limited to, environmental destruction, illegal wildlife trade, and increasingly intensive livestock and poultry production. It is high time that humans look into efforts that prevent the emergence of these illnesses, rather than simply managing their effects. Addressing the problem through the lens of One Health is the way to go.
Veterinary Integrative Sciences, May 6, 2021
Foodborne trematodiasis is a neglected tropical disease (NTD) caused by zoonotic trematodes that ... more Foodborne trematodiasis is a neglected tropical disease (NTD) caused by zoonotic trematodes that persist mainly in impoverished areas in the Asia-Pacific region. Globally, about 2 million disability life years (DALYs) are lost due to these parasitic infections. Four groups of foodborne trematodes are known to cause significant illness: fish-borne liver fluke infections caused by Opisthorchis and Clonorchis spp.; water vegetable-borne Fasciola spp. infections; crustacean-vectored paragonimiasis; and those caused by intestinal trematodes. In the Philippines, endemic foodborne trematodes of public health concern include Paragonimus westermani, some members of Heterophyidae and Echinostomatidae, and Fasciola hepatica/ F. gigantica. Opisthorchis viverrini and Clonorchis sinensis have also been reported in the country. Data on the epidemiology of these zoonotic illnesses remain scarce and in need of research attention in the Philippines. Culturally rooted eating behaviors in endemic areas are important risk factors to acquiring and perpetuating foodborne trematodiasis. The combination of mass drug administration (MDA), provision of clean water and maintenance of good sanitation and hygiene (WASH), community health education towards modification of risky behaviors, surveillance, and veterinary public health interventions have been shown to be effective in combatting these zoonotic parasitoses. An integrated control and prevention program anchored on the One Health paradigm is a must to address these illnesses. This paper aims to review the biology and epidemiology of, and public health interventions against zoonotic foodborne trematodiasis in the Philippines and its neighboring countries.
Schistosoma japonicum infections continue to be a public health concern in China, the Philippines... more Schistosoma japonicum infections continue to be a public health concern in China, the Philippines, and Indonesia. In the Philippines, it has a focal distribution wherein an estimated 12.4 million people are at risk of infection, while 2.7 million are directly exposed across 12 regions. The country’s latest national prevalence revealed that some endemic communities had already reached infection control status. Recent advancements in schistosomiasis diagnostics have resulted in the development of assays that have superior diagnostic performance. The cost of adopting these novel techniques remains a huge bottleneck for those with developing economies and underfunded control and elimination programs like the Philippines. Mass Drug Administration (MDA) has significantly reduced the schistosomiasis morbidity rates in the Philippines through its protracted implementation. MDA fatigue among beneficiaries resulting in non-compliance has been reported. Control and elimination efforts still need continued local and national governmental support. A One Health approach is called for if the goal of transmission interruption in all endemic communities is to be achieved by 2025. This paper reviews the recent research and updates on S. japonicum infections in terms of disease occurrence, advancements in diagnostic techniques and approaches, and its treatment, prevention, control, and elimination in the Philippines and its neighboring countries.
Journal of Agricultural Research, Development, Extension and Technology, Oct 8, 2021
Schistosoma japonicum infections continue to be a public health concern in China, the Philippines... more Schistosoma japonicum infections continue to be a public health concern in China, the Philippines, and Indonesia. In the Philippines, it has a focal distribution wherein an estimated 12.4 million people are at risk of infection, while 2.7 million are directly exposed across 12 regions. The country’s latest national prevalence revealed that some endemic communities had already reached infection control status. Recent advancements in schistosomiasis diagnostics have resulted in the development of assays that have superior diagnostic performance. The cost of adopting these novel techniques remains a huge bottleneck for those with developing economies and underfunded control and elimination programs like the Philippines. Mass Drug Administration (MDA) has significantly reduced the schistosomiasis morbidity rates in the Philippines through its protracted implementation. MDA fatigue among beneficiaries resulting in non-compliance has been reported. Control and elimination efforts still need continued local and national governmental support. A One Health approach is called for if the goal of transmission interruption in all endemic communities is to be achieved by 2025. This paper reviews the recent research and updates on S. japonicum infections in terms of disease occurrence, advancements in diagnostic techniques and approaches, and its treatment, prevention, control, and elimination in the Philippines and its neighboring countries.
International journal of one health, 2020
Background and Aim: Schistosomiasis is one of the seven neglected tropical diseases that are of p... more Background and Aim: Schistosomiasis is one of the seven neglected tropical diseases that are of public health concern in the Philippines. The disease is prevalent in few of the barangays (communities) in Koronadal City, Philippines. Status of the Schistosoma japonicum infections in domestic animal reservoir host has yet to be explored in these endemic communities. The study aimed to determine the prevalence and infection intensity of the disease in cattle and water buffaloes of endemic communities of Koronadal City. Materials and Methods: Schistosomiasis was investigated in 70 cattle and 38 water buffaloes from three endemic communities in Koronadal City. The copro-parasitological technique used was the formalin-ethyl acetate sedimentation method. Results: S. japonicum infection was observed in 48.6% of cattle and 60.5% in water buffaloes. The bovine contamination index indicated that all infected animals released 3,505,500 eggs/day. On average, infected cattle released 1,674,500 eggs daily, while infected water buffaloes liberated 1,932,000 eggs in the environment daily. Conclusion: Cattle and water buffaloes in these endemic areas are infected with S. japonicum. These animals release large numbers of eggs in the environment daily; hence, played an important role in disease transmission. Those living and working in endemic areas should be aware of the inherent dangers of the disease.
Journal of Livestock Science
Disease does not occur randomly. There are always epidemiologic patterns that are related to the ... more Disease does not occur randomly. There are always epidemiologic patterns that are related to the individuals at risk, the place at which risk is highest, and the time during which acquiring the disease is of the highest risk. Epidemiologic transition describes the transition of population distributions as it relates to shifting mortality, fertility, life expectancy, and the changing causes of death as time goes by. Prevalence measures the proportion of diseased individuals relative to the population at risk at a specified point or period of time, meanwhile, incidence only considers new or incident cases and thus the development of disease during the study is observable. Odds ratio (OR), as the name implies, compares the odds of exposure to the factor between diseased and non-diseased persons. Risk ratio or relative risks (RR) compares the probability of disease development between the exposed and non-exposed groups. Population attributable risk (PAR) is a measure of exposure effect that is specifically used to quantify the risk of disease in a population that is attributable to the suspected risk factor, while population attributable fraction (PAF), which is the proportion of sick individuals in the population that is due to exposure to the factor. Quality-adjusted life years (QALY) and disability-adjusted life years (DALY) are population health measures that aim to quantify the effect of disease morbidity and mortality within a single number. The objective of the paper is to introduce novice veterinary public health researchers to these fundamental epidemiological concepts.
Journal of Livestock Science, 2023
Disease does not occur randomly. There are always epidemiologic patterns that are related to the ... more Disease does not occur randomly. There are always epidemiologic patterns that are related to the individuals at risk, the place at which risk is highest, and the time during which acquiring the disease is of the highest risk. Epidemiologic transition describes the transition of population distributions as it relates to shifting mortality, fertility, life expectancy, and the changing causes of death as time goes by. Prevalence measures the proportion of diseased individuals relative to the population at risk at a specified point or period of time, meanwhile, incidence only considers new or incident cases and thus the development of disease during the study is observable. Odds ratio (OR), as the name implies, compares the odds of exposure to the factor between diseased and non-diseased persons. Risk ratio or relative risks (RR) compares the probability of disease development between the exposed and non-exposed groups. Population attributable risk (PAR) is a measure of exposure effect that is specifically used to quantify the risk of disease in a population that is attributable to the suspected risk factor, while population attributable fraction (PAF), which is the proportion of sick individuals in the population that is due to exposure to the factor. Quality-adjusted life years (QALY) and disability-adjusted life years (DALY) are population health measures that aim to quantify the effect of disease morbidity and mortality within a single number. The objective of the paper is to introduce novice veterinary public health researchers to these fundamental epidemiological concepts.
Journal of livestock science, Apr 8, 2022
Risk is a probability that an unfavorable event or harm (e.g., illness) will occur due to exposur... more Risk is a probability that an unfavorable event or harm (e.g., illness) will occur due to exposure to a hazard. Hazard is the agent or factor that brings about harm. It may be a pathogenic agent, a characteristic of an individual or of the herd, or some extrinsic factors (e.g., the environment) that causes or increases the likelihood of harm. Harm may be an unfavorable health eventuality or a dire consequence that is caused by specific hazards and risks. When we consider these three interwoven concepts, we get Risk Analysis. Risk analysis has several interconnected components: Hazard Identification, Risk Assessment, Risk Management and Risk Communication. Risk analysis, as a framework of assessing the likelihood, causes and consequences of unwanted health related phenomenon, is very important in discussing zoonotic infectious diseases (e.g., Bovine Spongiform Encephalopathy and Highly Pathogenic Avian Influenza), laboratory biosecurity and biorisk management and disease prioritization. At the core of this principle and framework is the aim of limiting the occurrence of a harmful consequence while keeping in mind the benefits of the planned and implemented management efforts. The aim of this article is to succinctly introduce risk analysis as a framework, its components, and its application in veterinary science and medicine.
Advances in Animal and Veterinary Sciences, 2022
One Health, as an approach to achieving important global health outcomes, thrives at the intersec... more One Health, as an approach to achieving important global health outcomes, thrives at the intersectionality of human health, veterinary health and environmental health. The interdependence of these three pillars highlights its importance as a holistic tool for inclusive development. With a prevailing pandemic that is caused by a zoonotic viral agent, One Health truly is the keyword of the times. Similarly, the numerous Neglected Tropical Diseases prevalent throughout the world also calls upon a One Health approach for their control, elimination and prevention. Public health veterinarians seek to keep communities safe and healthy by promoting human and environmental health through preserving animal health. As a panopticon to view the achievement of vital global health outcomes, One Health is truly a collaborative affair. The paradigm, by definition, is multidisciplinary, multi-sectoral, and integrative in nature. Thus, effective collaborations and partnerships towards understanding are integral to successful programs. Moreover, how a One Health institution thrives is heavily reliant on how the separate, yet interconnected branches effectively communicate to each other. The aim of this paper is to consider some One Health points of discussion that are worthy of highlighting despite their pretermit nature. Discussions on One Health as a lens in viewing NTDs in the Philippines, an appreciation of veterinary public health as veterinary medicine's entry point to One Health, the importance of effective communication, collaborations and partnerships within the paradigm are subsumed herein.
Microbes, Infection and Chemotherapy, 2022
Journal of Livestock Science, 2022
Postmortem examination of food animals during slaughter enables the identification of illnesses a... more Postmortem examination of food animals during slaughter enables the identification of illnesses and health issues that subvert the quality of carcasses and offal. Gross pathological lesions seen at slaughter have important economic impact and implications on the Halal wholesomeness of these food items, and therefore there is a need to identify them. The study identified and described the gross pathological lesions found on the livers and kidneys of cattle slaughtered in a Halal abattoir in Cotabato City, Philippines from December 12, 2020 to January 28, 2021. A total of seventy (70) cattle were included in the study: 70 livers and 140 kidneys were collected and examined. The lesions identified in the bovine livers included fibrosis (15.71%), cholangitis (15.71%), liver fluke migratory tracts (1.43%), and cirrhosis (2.9%). Among the kidneys examined, white spotted kidneys (10.71%), renal infarcts (10.71%), renal atrophy (6.43%), amyloidosis (5.71%), ecchymosis (4.29%), myoglobinuria (2.86%), hydronephrosis (2.86%), pyelonephritis (2.14%) and renal cyst (1.43%) were the lesions seen. Numerous gross pathological lesions were identified among the livers and kidneys assessed in the current study. Production and health management practices must be improved if the occurrence of these economically important pathological lesions is to be reduced.
Journal of Livestock Science, 2022
The accelerated pace at which human development has been set into has resulted into fast-tracking... more The accelerated pace at which human development has been set into has resulted into fast-tracking the emergence of novel diseases that affect both humans and animals. One of these is the emergence of infectious zoonotic diseases that have threatened human health since time immemorial. The emergence of Highly Pathogenic Avian Influenza (HPAI) H5:N1 from poultry in 2002, Severe acute respiratory syndrome coronavirus (SARS-CoV) from civets and bats in 2003, Middle East Respiratory Syndrome coronaviruses (MERS-CoV) from camelids in 2014, and most recently in SARS-CoV 2 or COVID-19, which reportedly came from bats, should serve as lessons that should be taken seriously. Factors that have resulted in the emergence of these illnesses include, but are not limited to, environmental destruction, illegal wildlife trade, and increasingly intensive livestock and poultry production. It is high time that humans look into efforts that prevent the emergence of these illnesses, rather than simply managing their effects. Addressing the problem through the lens of One Health is the way to go.
Philippine Journal of Veterinary Medicine, 2021
Schistosomiasis is a Neglected Tropical Disease (NTD) that persists in 78 countries around the wo... more Schistosomiasis is a Neglected Tropical Disease (NTD) that persists in 78 countries around the world. Schistosoma japonicum infections persist as a public health concern in China, the Philippines, and Indonesia. In the Philippines, it is endemic in 1,609 barangays across 12 regions, with about 12.4 million Filipinos at risk and 2.7 million exposed to infections. Many studies have reported the disease’s epidemiology among different animal reservoirs in endemic areas in the country. High infection prevalences have also been reported among water buffaloes in endemic hotspots, suggesting that they are the major zoonotic reservoir of infections. The status of schistosomiasis in bubaline reservoir hosts remains largely unknown in the rest of the endemic foci. The adverse economic effects of livestock infections have been documented in China, but the extent and value of these production losses due to infections remain unknown in the Philippines. Schistosomiasis’ zoonotic nature highlights the importance of Veterinary Public Health with One Health in approaching its prevention, control and elimination. This article aims to collate the published literature on animal S. japonicum infections in the Philippines to draw attention to its veterinary public health importance and to mitigate the sparse attention the disease gets from the Filipino veterinary community.
Journal of Agricultural Research, Development, Extension, and Technology, 2021
Schistosoma japonicum infections continue to be a public health concern in China, the Philippines... more Schistosoma japonicum infections continue to be a public health concern in China, the Philippines, and Indonesia. In the Philippines, it has a focal distribution wherein an estimated 12.4 million people are at risk of infection, while 2.7 million are directly exposed across 12 regions. The country’s latest national prevalence revealed that some endemic communities had already reached infection control status. Recent advancements in schistosomiasis diagnostics have resulted in the development of assays that have superior diagnostic performance. The cost of adopting these novel techniques remains a huge bottleneck for those with developing economies and underfunded control and elimination programs like the Philippines. Mass Drug Administration (MDA) has significantly reduced the schistosomiasis morbidity rates in the Philippines through its protracted implementation. MDA fatigue among beneficiaries resulting in non-compliance has been reported. Control and elimination efforts still need continued local and national governmental support. A One Health approach is called for if the goal of transmission interruption in all endemic communities is to be achieved by 2025. This paper reviews the recent research and updates on S. japonicum infections in terms of disease occurrence, advancements in diagnostic techniques and approaches, and its treatment, prevention, control, and elimination in the Philippines and its neighboring countries.
Journal of Current Science and Technology, 2021
Campylobacteriosis is one of the four primary etiologies of foodborne diarrheal illnesses globall... more Campylobacteriosis is one of the four primary etiologies of foodborne diarrheal illnesses globally. The disease affects 1 out of 10 individuals worldwide, with 33 million life years lost annually. There is evidence that campylobacteriosis is increasing in its occurrence in developed countries, but research is lacking in those with developing economies such as the Philippines. Of the 34 Campylobacter species known to date, C. jejuni subsp. jejuni and C. coli are the most common case isolates. These bacteria are commensals of the intestinal tract of animals, among which, chickens and their meats have been implicated as the primary source of human campylobacteriosis. All the components of the poultry production chain contribute to the zoonotic transmission of the foodborne pathogen. Inadequate farm biosecurity measures and unsanitary dressing procedures bleed into high contamination loads of chicken meats at the market and consumer levels. Attempts to decrease C. jejuni in poultry include rearing and management modifications, alterations in slaughter and dressing procedures, novel packaging technologies, and hygienic practices in food preparation. Antimicrobial resistance of C. jejuni has been increasingly reported globally. On the veterinary public health front, studies are needed to continuously assess C. jejuni as a pathogen in the poultry production line and the consumer level. This paper reviewed C. jejuni as a foodborne pathogen and its close association with chicken meat as its food vehicle of infection.
Journal on New Biological Reports, 2021
Lymnaeid snail infestation and snail-borne parasitic diseases, such as fasciolosis, remain a prob... more Lymnaeid snail infestation and snail-borne parasitic diseases, such as fasciolosis, remain a problem in the livestock industry in the Philippines. Effective molluscicides are thus needed. However, the routine application of commercially available molluscicides may cause unwanted environmental contamination. Natural alternatives to commercially available molluscicides are called for, thus, this study investigated the molluscicidal activity and efficacy of makabuhay (T. rumphii) ethanolic stem extract against lymnaeid snails. A total of 150 mature snails from Barangay Guiamalia, Esperanza, Sultan Kudarat were subjected to immersion bioassay with T. rumphii ethanolic extracts. There were five treatment groups: Treatment A or negative control (100% tap water), Treatment B (5 000 ppm), Treatment C (7 500 ppm), Treatment D (10 000 ppm) and Treatment E or positive control (10 000 ppm Surekill® 70WP). Snail death was measured 24-, 48- and 72- hours post-exposure. The results revealed a 100% treatment-specific mortality in all T. rumphii extract concentrations, and in the positive control at 24-hours post-treatment. Treatments B, C, D and E had an excellent efficacy of 96.67%. These results show that T. rumphii ethanolic extracts at 5 000 ppm, 7 500 ppm and 10 000 ppm concentrations are effective natural molluscicides against lymnaeid snails. The promising results suggest that T. rumphii stem ethanolic extract may be an excellent natural, inexpensive alternative to commercially available molluscicides.
Veterinary Integrative Sciences, 2021
Foodborne trematodiasis is a neglected tropical disease (NTD) caused by zoonotic trematodes that ... more Foodborne trematodiasis is a neglected tropical disease (NTD) caused by zoonotic trematodes that persist mainly in impoverished areas in the Asia-Pacific region. Globally, about 2 million disability life years (DALYs) are lost due to these parasitic infections. Four groups of foodborne trematodes are known to cause significant illness: fish-borne liver fluke infections caused by Opisthorchis and Clonorchis spp.; water vegetable-borne Fasciola spp. infections; crustacean-vectored paragonimiasis; and those caused by intestinal trematodes. In the Philippines, endemic foodborne trematodes of public health concern include Paragonimus westermani, some members of Heterophyidae and Echinostomatidae, and Fasciola hepatica/ F. gigantica. Opisthorchis viverrini and Clonorchis sinensis have also been reported in the country. Data on the epidemiology of these zoonotic illnesses remain scarce and in need of research attention in the Philippines. Culturally rooted eating behaviors in endemic areas are important risk factors to acquiring and perpetuating foodborne trematodiasis. The combination of mass drug administration (MDA), provision of clean water and maintenance of good sanitation and hygiene (WASH), community health education towards modification of risky behaviors, surveillance, and veterinary public health interventions have been shown to be effective in combatting these zoonotic parasitoses. An integrated control and prevention program anchored on the One Health paradigm is a must to address these illnesses. This paper aims to review the biology and epidemiology of, and public health interventions against zoonotic foodborne trematodiasis in the Philippines and its neighboring countries.
Uploads
Papers by Jan Clyden B. Tenorio
Materials and Methods: Using AlphaFold 3, the α- and β-tubulin amino acid sequences of Ancylostoma ceylanicum were used to predict the structural fold of the hookworm tubulin heterodimer. The modeled complexes were subjected to several protein structure quality assurance checks. The binding free energies, overall binding affinity, dissociation constant, and interacting amino acids of the complex were determined. The dimer’s structural flexibility and motion were simulated through molecular dynamics.
Results: BZ resistance-associated amino acid substitutions in the β-tubulin isotype 1 protein of hookworms altered tubulin dimerization. The E198K, E198V, and F200Y mutations conferred the strongest and most stable binding between the α and β subunits, surpassing that of the wild-type. In contrast, complexes with the Q134H and F200L mutations exhibited the opposite effect. Molecular dynamics simulations showed that wild-type and mutant tubulin dimers exhibited similar dynamic behavior, with slight deviations in those carrying the F200L and E198K mutations.
Conclusion: Resistance-associated mutations in hookworms impair BZ binding to β-tubulin and enhance tubulin dimer interactions, thereby increasing the parasite’s ability to withstand treatment. Conversely, other mutations weaken these interactions, potentially compromising hookworm viability. These findings offer novel insights into helminth tubulin dimerization and provide a valuable foundation for developing anthelmintics targeting this crucial biological process.
Keywords: Ancylostoma, anthelmintic resistance, microtubules, soil-transmitted helminths.
Materials and Methods: Using AlphaFold 3, the α- and β-tubulin amino acid sequences of Ancylostoma ceylanicum were used to predict the structural fold of the hookworm tubulin heterodimer. The modeled complexes were subjected to several protein structure quality assurance checks. The binding free energies, overall binding affinity, dissociation constant, and interacting amino acids of the complex were determined. The dimer’s structural flexibility and motion were simulated through molecular dynamics.
Results: BZ resistance-associated amino acid substitutions in the β-tubulin isotype 1 protein of hookworms altered tubulin dimerization. The E198K, E198V, and F200Y mutations conferred the strongest and most stable binding between the α and β subunits, surpassing that of the wild-type. In contrast, complexes with the Q134H and F200L mutations exhibited the opposite effect. Molecular dynamics simulations showed that wild-type and mutant tubulin dimers exhibited similar dynamic behavior, with slight deviations in those carrying the F200L and E198K mutations.
Conclusion: Resistance-associated mutations in hookworms impair BZ binding to β-tubulin and enhance tubulin dimer interactions, thereby increasing the parasite’s ability to withstand treatment. Conversely, other mutations weaken these interactions, potentially compromising hookworm viability. These findings offer novel insights into helminth tubulin dimerization and provide a valuable foundation for developing anthelmintics targeting this crucial biological process.
Keywords: Ancylostoma, anthelmintic resistance, microtubules, soil-transmitted helminths.