Unraveling the mechanisms of benzimidazole resistance in hookworms: A molecular docking and dynamics study

被引:0
|
作者
Tenorio, Jan Clyden B. [1 ,2 ]
Heikal, Muhammad Fikri [1 ]
Kafle, Alok [1 ]
Macalalad, Mark Andrian B. [3 ]
Orosco, Fredmoore L. [3 ,4 ,5 ]
Saichua, Prasert [6 ,7 ]
Suttiprapa, Sutas [6 ,7 ]
机构
[1] Khon Kaen Univ, Fac Med, Dept Trop Med, Trop Med Grad Program, Khon Kaen 40002, Thailand
[2] Univ Southern Mindanao, Coll Vet Med, Dept Vet Paraclin Sci, Cotabato 9407, Philippines
[3] Ind Technol Dev Inst, Dept Sci & Technol, Virol & Vaccine Res & Dev Program, Taguig City 1631, Metro Manila, Philippines
[4] S&T Fellows Program, Dept Sci & Technol, Taguig City 1631, Metro Manila, Philippines
[5] Univ Philippines Manila, Coll Arts & Sci, Dept Biol, Manila 1000, Metro Manila, Philippines
[6] Khon Kaen Univ, Fac Med, Dept Trop Med, Khon Kaen 40002, Thailand
[7] Khon Kaen Univ, WHO Collaborating Ctr Res & Control Opisthorchiasi, Trop Dis Res Ctr, Khon Kaen 40002, Thailand
来源
JOURNAL OF GENETIC ENGINEERING AND BIOTECHNOLOGY | 2025年 / 23卷 / 01期
关键词
Antimicrobial Resistance; Deworming; Ancylostoma; Necator; Neglected Tropical Diseases; BETA-TUBULIN GENE; SYSTEMATIC ANALYSIS; GLOBAL BURDEN; 195; COUNTRIES; BINDING-SITE; TERRITORIES; PREVALENCE; DISABILITY; INJURIES; INSIGHTS;
D O I
10.1016/j.jgeb.2025.100472
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
Background: Benzimidazole resistance is an emerging challenge among parasitic helminths. It is caused by single nucleotide polymorphisms (SNPs) in specific loci in helminths' beta-tubulin genes. Field studies and laboratory investigations reported resistance-associated SNPs in 4 codon locations with 7 allelic variations among hookworms. This study aimed to determine the effects of these mutations on the binding efficiency and behavior of the beta-tubulin protein in four hookworm species against four benzimidazole drugs. Methods: beta-tubulin gene coding sequences of Ancylostoma caninum, A. duodenale, A. ceylanicum, and Necator americanus were retrieved, assessed phylogenetically, and used to construct the 3D structure models of the proteins. The modeled protein structures were verified and edited to contain the reported SNPs: Q134H, F167Y, E198A, E198K, E198V, F200L, and F200Y. Benzimidazole drugs such as albendazole (ABZ), fenbendazole (FBZ), mebendazole (MBZ) and oxfendazole (OBZ) were used as ligands. Molecular docking experiments were performed with the wild-type and mutated proteins. Molecular dynamics simulation assessed the dynamic behavior of the beta-tubulin-benzimidazole complex. Results: In silico docking assessments showed that various amino acid substitutions due to resistance-associated SNPs cause alterations in binding affinities and positions. E198K and Q134H in hookworm beta-tubulins substantially weakened the binding affinities and altered the binding positions of benzimidazole drugs. Molecular dynamics analysis revealed that these mutations also caused marked reductions in the binding free energies owing to diminished hydrogen bond contacts with the benzimidazole ligands. Conclusion: The evidence shown herein indicates that mutations at positions 198 and 134 are detrimental to conferring benzimidazole resistance among hookworms. The presence of these mutations may alter the efficacy of pharmacological interventions. Hence, further studies should be conducted to assess their emergence among hookworms in endemic areas with histories of chemotherapy.
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页数:11
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