scholarly journals UDP-Glycosyltransferases and Albendazole Metabolism in the Juvenile Stages of Haemonchus contortus

2020 ◽  
Vol 11 ◽  
Author(s):  
Pavlína Kellerová ◽  
Martina Navrátilová ◽  
Linh Thuy Nguyen ◽  
Diana Dimunová ◽  
Lucie Raisová Stuchlíková ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Resistant Strain ◽  
Haemonchus Contortus ◽  
Resistance Mechanism ◽  
Constitutive Expression ◽  
Primary Metabolite ◽  
Resistance Development ◽  
Enhanced Solubility ◽  
Juvenile Stages ◽  
Resistant Strains

The nematode Haemonchus contortus, a gastrointestinal parasite of ruminants, can severely burden livestock production. Although anthelmintics are the mainstay in the treatment of haemonchosis, their efficacy diminishes due to drug-resistance development in H. contortus. An increased anthelmintics inactivation via biotransformation belongs to a significant drug-resistance mechanism in H. contortus. UDP-glycosyltransferases (UGTs) participate in the metabolic inactivation of anthelmintics and other xenobiotic substrates through their conjugation with activated sugar, which drives the elimination of the xenobiotics due to enhanced solubility. The UGTs family, in terms of the biotransformation of commonly used anthelmintics, has been well described in adults as a target stage. In contrast, the free-living juvenile stages of H. contortus have attracted less attention. The expression of UGTs considerably varies throughout the life cycle of the juvenile nematodes, suggesting their different roles. Furthermore, the constitutive expression in a susceptible strain with two resistant strains shows several resistance-related changes in UGTs expression, and the exposure of juvenile stages of H. contortus to albendazole (ABZ) and ABZ-sulfoxide (ABZSO; in sublethal concentrations) leads to the increased expression of several UGTs. The anthelmintic drug ABZ and its primary metabolite ABZSO biotransformation, tested in the juvenile stages, shows significant differences between susceptible and resistant strain. Moreover, higher amounts of glycosidated metabolites of ABZ are formed in the resistant strain. Our results show similarly, as in adults, the UGTs and glycosidations significant for resistance-related differences in ABZ biotransformation and warrant further investigation in their individual functions.

scholarly journals Tandem Repeat of a Transcriptional Enhancer Upstream of the Sterol 14α-Demethylase Gene (CYP51) inPenicillium digitatum

2000 ◽  
Vol 66 (8) ◽  
pp. 3421-3426 ◽  
Author(s):  
Hiroshi Hamamoto ◽  
Koji Hasegawa ◽  
Ryoji Nakaune ◽  
Young Jin Lee ◽  
Yoshiyuki Makizumi ◽  
...  
Keyword(s):  
Filamentous Fungi ◽  
Tandem Repeat ◽  
Resistant Strain ◽  
Fungicide Resistance ◽  
Promoter Region ◽  
Resistance Mechanism ◽  
Constitutive Expression ◽  
Structural Genes ◽  
Transcriptional Enhancer ◽  
Resistant Strains

ABSTRACT We investigated the mechanism of resistance to demethylation inhibitors (DMI) in Penicillium digitatum by isolating theCYP51 gene, which encodes the target enzyme (P45014DM) of DMI, from three DMI-resistant and three DMI-sensitive strains. The structural genes of all six strains were identical, but in the promoter region, a unique 126-bp sequence was tandemly repeated five times in the DMI-resistant strains and was present only once in the DMI-sensitive strains. Constitutive expression of CYP51 in the resistant strains was about 100-fold higher than that in the sensitive strains. We introduced CYP51, including the promoter region, from a DMI-resistant strain into a DMI-sensitive strain, which rendered the transformants DMI resistant and increased CYP51 expression. We also found that if the number of copies of the repeat was reduced to two, resistance andCYP51 expression also decreased. These results indicate that the 126-bp unit acts as a transcriptional enhancer and that a tandem repeat of the unit enhances CYP51 expression, resulting in DMI resistance. This is a new fungicide resistance mechanism for filamentous fungi.

scholarly journals Drug Resistance Mechanism among Acinetobacter Species

2021 ◽  
Author(s):  
S. Jayashree ◽  
K.G. Rajeshwari ◽  
Mita D. Wadekar
Keyword(s):  
Drug Resistance ◽  
Resistance Mechanism ◽  
Multidrug Resistant ◽  
Hospital Environment ◽  
Diffusion Method ◽  
Multi Drug Resistance ◽  
Intrinsic Resistance ◽  
Acinetobacter Species ◽  
Beta Lactamases ◽  
Resistant Strains

Acinetobacter species cause infections that are difficult to control due to multi-drug resistance and are noted for their intrinsic resistance to antibiotics and for their ability to acquire genes encoding resistance for the production of beta-lactamases and Aminoglycoside-modifying enzymes. MBLs are molecular class B and functional group 3 beta-lactamases which have the capability of hydrolyzing all β-lactams except the Monobactam, Aztreonam. Of several MBLs, only IMP, VIM and SIM types have been detected in these species. To analyze the antibiotic resistance patterns among Acinetobacter isolates and to detect Carbapenemase and MBL among MDR Acinetobacter isolates. The descriptive study of all phenotypically identified strains and multidrug-resistant strains of Acinetobacter species was conducted. A total of 303 isolates were isolated from various samples. They were processed and identified by standard Microbiological procedures. The antibiotics susceptibility testing was performed by Kirby- Bauer disc diffusion method using CLSI guidelines. Carbapenemase production was detected by employing 3 phenotypic test methods (MHT, CDM and DDST). Of 6355 samples processed, 303 were found to be Acinetobacter species, among those 50 were multidrug-resistant strains. The highest isolation of MDR Acinetobacter was from endotracheal tube tip (42%) and pus sample (32%). The majority of MDR Acinetobacter infection was found in male patients 36 (72%) compared to female patients 14 (28%). The majority of the strains were isolated from patients >/ 60 years of age group (%). A number of these isolates were more from ICU wards (30%) followed by Surgery wards (24%). Higher resistance for the Piperacillin/tazobactam ((82%), followed by Ceftazidime (80%), Imipenem (76%) etc. and the most susceptible drug was found to be the Tigecycline (82%) followed by Colistin (80%). Carbapenemase production was detected by MHT and 24 (48%) isolates were MHT positive. MBL production was detected by CDM and 34 (68%) isolates were CDM positive and by DDST 30 (60%) isolates were positive. Acinetobacter species are increasingly important nosocomial pathogens and are capable of rapid adaptation to the hospital environment. The variety of potential source of contamination or infection with these species in the hospital environment makes control of outbreaks caused by these difficult.

scholarly journals Sertraline as a new potential anthelmintic against Haemonchus contortus: toxicity, efficacy, and biotransformation

2021 ◽  
Vol 52 (1) ◽  
Author(s):  
Markéta Zajíčková ◽  
Lukáš Prchal ◽  
Martina Navrátilová ◽  
Nikola Vodvárková ◽  
Petra Matoušková ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Haemonchus Contortus ◽  
Metabolic Pathways ◽  
Parasitic Nematode ◽  
Parasitic Nematodes ◽  
Main Metabolite ◽  
Egg Hatching ◽  
Trichuris Muris ◽  
Resistant Strains ◽  
Potential Hepatotoxicity

AbstractHaemonchus contortus is a parasitic nematode of ruminants which causes significant losses to many farmers worldwide. Since the drugs currently in use for the treatment of haemonchosis are losing their effectiveness due to the drug-resistance of this nematode, a new or repurposed drug is highly needed. As the antipsychotic drug sertraline (SRT) has been shown to be effective against the parasitic nematodes Trichuris muris, Ancylostoma caninum and Schistosoma mansoni, the aim of the present study was to evaluate the possible effect of SRT on H. contortus. The potential hepatotoxicity of SRT was tested in sheep, a common H. contortus host. In addition, the main metabolic pathways of SRT in H. contortus and the ovine liver were identified. While no effect of SRT on H. contortus egg hatching was observed, SRT was found to significantly decrease the viability of H. contortus adults in drug-sensitive and resistant strains, with its effect comparable to the commonly used anthelmintics levamisole and monepantel. Moreover, SRT in anthelmintically active concentrations showed no toxicity to the ovine liver. Biotransformation of SRT in H. contortus was weak, with most of the drug remaining unmetabolized. Production of the main metabolite hydroxy-SRT did not differ significantly between strains. Other minor metabolites such as SRT-O-glucoside, dihydroxy-SRT, and SRT-ketone were also identified in H. contorts adults. Compared to H. contortus, the ovine liver metabolized SRT more extensively, mainly via desmethylation and glucuronidation. In conclusion, the potency of SRT against H. contortus was proven, and it should be tested further toward possible repurposing.

The development of resistance to glycarbylamide and 2-chloro-4-nitrobenzamide in Eimeria tenella in chicks

Parasitology ◽  
1966 ◽  
Vol 56 (1) ◽  
pp. 25-37 ◽  
Author(s):  
S. J. Ball
Keyword(s):  
Drug Resistance ◽  
Resistant Strain ◽  
Parent Strain ◽  
Technical Assistance ◽  
Eimeria Tenella ◽  
Single Test ◽  
Normal Parent ◽  
Twofold Increase ◽  
Development Of Resistance ◽  
Resistant Strains

A twofold increase in resistance to glycarbylamide was induced in a strain of Eimeria tenella in chicks. This strain remained susceptible to amprolium, nicarbazin, nitrofurazone, zoalene, 3,5-dinitrobenzamide, 2-chloro-4-nitrobenzamide (M & B 5921) and spiramycin.At least an eightfold resistance to 2-chloro-4-nitrobenzamide (M & B 5921) was developed in another strain of E. tenella. This strain was also resistant to nitrofurazone, zoalene and 3,5-dinitrobenzamide, but not to glycarbylamide, amprolium, nicarbazin and spiramycin.A single test showed no transfer of drug-resistance when the two resistant strains were given simultaneously to the same birds.When a small number of parasites of a glycarbylamide-resistant strain of E. tenella was introduced into a larger inoculum of the normal parent strain, the resistant individuals appeared to diminish in number during passages through untreated chicks.I wish to thank Mrs B. M. Mitchell, Miss C. A. Hitchcock and Miss J. Watkins for technical assistance at various stages of the work.

scholarly journals Polygenic and single gene responses to selection for resistance to diazinon in Lucilia cuprina.

Genetics ◽  
1992 ◽  
Vol 130 (3) ◽  
pp. 613-620 ◽  
Author(s):  
J A McKenzie ◽  
A G Parker ◽  
J L Yen
Keyword(s):  
Resistant Strain ◽  
Single Gene ◽  
Natural Populations ◽  
Susceptible Strain ◽  
Selection Line ◽  
Base Population ◽  
Gene Response ◽  
Biochemical Profiles ◽  
Resistant Strains ◽  
Selection For

Abstract Following mutagenesis with ethyl methanesulfonate, selection in a susceptible strain with a concentration of the insecticide diazinon (0.0004%, w/v) above that required to kill 100% of the susceptible strain, the LC100 of that strain, resulted in a single gene response. The resultant four mutant resistant strains have equivalent physiological, genetical and biochemical profiles to a diazinon-resistant strain derived from a natural population and homozygous for the Rop-1 allele. Modification of the microsomal esterase E3 is responsible for resistance in each case. The Rop-1 locus maps approximately 4.4 map units proximal to bu on chromosome IV. Selection within the susceptible distribution, at a concentration of diazinon [0.0001% (w/v)] less than the LC100, resulted in a similar phenotypic response irrespective of whether the base population had been mutagenized. The responses were polygenically based, unique to each selection line and independent of Rop-1. The relevance of the results to selection for insecticide resistance in laboratory and natural populations is discussed.

scholarly journals Structural Investigation and Molecular Modeling Studies of Strobilurin-Based Fungicides Active against the Rice Blast Pathogen Pyricularia oryzae

2021 ◽  
Vol 22 (7) ◽  
pp. 3731
Author(s):  
Andrea Kunova ◽  
Luca Palazzolo ◽  
Fabio Forlani ◽  
Giorgia Catinella ◽  
Loana Musso ◽  
...  
Keyword(s):  
Rice Blast ◽  
Rational Design ◽  
Structural Investigation ◽  
Resistance Mechanism ◽  
Three Dimensional ◽  
Pyricularia Oryzae ◽  
Cytochrome Bc1 ◽  
Cytochrome Bc1 Complex ◽  
Three Dimensional Model ◽  
Resistant Strains

The increasing emergence of fungicide-resistant pathogens requires urgent solutions for crop disease management. Here, we describe a structural investigation of new fungicides obtained by combining strobilurin and succinate dehydrogenase inhibitor pharmacophores. We identified compounds endowed with very good activity against wild-type Pyricularia oryzae, combined in some cases with promising activity against strobilurin-resistant strains. The first three-dimensional model of P. oryzae cytochrome bc1 complex containing azoxystrobin as a ligand was developed. The model was validated with a set of commercially available strobilurins, and it well explains both the resistance mechanism to strobilurins mediated by the mutation G143A and the activity of metyltetraprole against strobilurin-resistant strains. The obtained results shed light on the key recognition determinants of strobilurin-like derivatives in the cytochrome bc1 active site and will guide the further rational design of new fungicides able to overcome resistance caused by G143A mutation in the rice blast pathogen.

scholarly journals Molecular modeling study on the drug resistance mechanism of NS5B polymerase to TMC647055

2016 ◽  
Vol 94 (2) ◽  
pp. 147-158 ◽  
Author(s):  
Huiqun Wang ◽  
Wei Cui ◽  
Chenchen Guo ◽  
Bo-Zhen Chen ◽  
Mingjuan Ji
Keyword(s):  
Drug Resistance ◽  
Free Energy ◽  
Rational Design ◽  
Binding Free Energy ◽  
Resistance Mechanism ◽  
Free Energy Calculations ◽  
Side Chain ◽  
Free Energy Decomposition ◽  
Hcv Ns5b ◽  
Ns5b Polymerase

NS5B polymerase plays an important role in viral replication machinery. TMC647055 (TMC) is a novel and potent non-nucleoside inhibitor of the HCV NS5B polymerase. However, mutations that result in drug resistance to TMC have been reported. In this study, we used molecular dynamics (MD) simulations, binding free energy calculations, and free energy decomposition to investigate the drug resistance mechanism of HCV to TMC resulting from L392I, P495T, P495S, and P495L mutations in NS5B polymerase. From the calculated results we determined that the decrease in the binding affinity between TMC and NS5BL392I polymerase is mainly caused by the extra methyl group at the CB atom of Ile. The polarity of the side-chain of residue 495 has no distinct influence on residue 495 binding with TMC, whereas the smaller size of the side-chain of residue 495 causes a substantial decrease in the van der Walls interaction between TMC and residue 495. Moreover, the longer length of the side-chain of residue 495 has a significant effect on the electrostatic interaction between TMC and Arg-503. Finally, we performed the same calculations and detailed analysis on other 3 mutations (L392V, P495V, and P495I). The results further confirmed our conclusions. The computational results not only reveal the drug resistance mechanism between TMC647055 and NS5B polymerase, but also provide valuable information for the rational design of more potent non-nucleoside inhibitors targeting HCV NS5B polymerase.

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