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 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 Pharmacodynamics and Dose-Response Relationships of Liposomal Amphotericin B against Different Azole-Resistant Aspergillus fumigatus Isolates in a Murine Model of Disseminated Aspergillosis

2013 ◽  
Vol 57 (4) ◽  
pp. 1866-1871 ◽  
Author(s):  
Seyedmojtaba Seyedmousavi ◽  
Willem J. G. Melchers ◽  
Johan W. Mouton ◽  
Paul E. Verweij
Keyword(s):  
Aspergillus Fumigatus ◽  
Dose Response ◽  
Tandem Repeat ◽  
Murine Model ◽  
Promoter Region ◽  
Liposomal Amphotericin ◽  
Resistance Mechanism ◽  
Azole Resistance ◽  
Wild Type ◽  
Content Type

ABSTRACTThe management of invasive aspergillosis (IA) has become more complicated due to the emergence of acquired azole resistance inAspergillus fumigatus, which is associated with treatment failure and a mortality rate of 88%. Treatment with liposomal amphotericin B (L-AmB) may be a useful alternative to improve therapeutic outcome in azole-resistant IA. Four clinicalA. fumigatusisolates obtained from patients with proven IA were studied in a nonneutropenic murine model of infection: a wild-type isolate without mutations in thecyp51Agene and three azole-resistant isolates harboring a single mutation at codon 220 (M220I) and tandem repeat mutations (a 34-bp tandem repeat mutation in the promoter region of thecyp51Agene in combination with substitutions at codon L98 [TR34/L98H] and a 46-bp tandem repeat mutation in the promoter region of thecyp51Agene in combination with mutation at codons Y121 and T289 [TR46/Y121F/T289A]), respectively. Female CD-1 mice were infected intravenously 24 h prior to the start of therapy. Groups of 11 mice were treated at days 1, 2, and 5 postchallenge with increasing 4-fold doses of L-AmB ranging from 0.004 to 16 mg/kg/day and observed for 14 days. Survival for all 4 isolates at day 14 was significantly better than that of controls. A dose-response relationship was observed independent of the azole resistance mechanism. The Hill-type model with a variable slope fitted the relationship between the dose and 14-day survival well for all isolates, withR2values of 0.95 (wild-type), 0.97 (M220I), 0.85 (TR34/L98H), and 0.94 (TR46/Y121F/T289A), respectively. Multiple logistic regression analysis confirmed that there was no significant difference between groups. The results of these experiments indicate that L-AmB was able to prolong survivalin vivoin disseminated IA independent of the presence of an azole resistance mechanism in a dose-dependent manner, and therefore, they support a role for L-AmB in the treatment of azole-resistant IA.

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 Assessing the Genome-Wide Effect of Promoter Region Tandem Repeat Natural Variation on Gene Expression

2012 ◽  
Vol 2 (12) ◽  
pp. 1643-1649 ◽  
Author(s):  
Martha H. Elmore ◽  
John G. Gibbons ◽  
Antonis Rokas
Keyword(s):  
Gene Expression ◽  
Tandem Repeat ◽  
Promoter Region ◽  
Natural Variation ◽  
Genome Wide

scholarly journals The Central Role of Multiple P450 Genes and Their Co-factor CPR in the Development of Permethrin Resistance in the Mosquito Culex quinquefasciatus

2022 ◽  
Vol 12 ◽  
Author(s):  
Youhui Gong ◽  
Ting Li ◽  
Qi Li ◽  
Shikai Liu ◽  
Nannan Liu
Keyword(s):  
Culex Quinquefasciatus ◽  
Resistance Mechanism ◽  
Gene Overexpression ◽  
Degradation Pathways ◽  
Cytochrome P450 Reductase ◽  
Major Threat ◽  
Development Of Resistance ◽  
Toxic Product ◽  
Resistant Strains

Mosquitoes’ increasing resistance to insecticides is becoming a major threat for control efforts worldwide. Multiple P450 genes that are up-regulated in permethrin resistant strains of Culex quinquefasciatus have been linked to the development of resistance. In the current study, we characterized the function of six P450 genes, CYP6P14, CYP6BZ2, CYP9J33, CYP9J34, CYP9J40, and CYP9J45, that are overexpressed in the permethrin resistant Culex mosquitoes and showed their capability in metabolism of permethrin. These six P450 genes can convert 3-phenoxybenzoic alcohol (PBCHO) to a less toxic product, 3-phenoxybenzoic acid (PBCOOH), indicating that these P450s play an important role in permethrin degradation pathways. Although we know multiple P450 genes are over-expressed in permethrin resistant Culex mosquitoes, it remains to be seen whether cytochrome P450-reductase (CPR) gene that are co-overexpressed with P450 genes in permethrin resistant mosquitoes do indeed serve as a resistance mechanism. An in-depth investigation of the expression of CPR gene in resistant mosquitoes was conducted in permethrin resistant mosquitoes. The finding of CPR gene overexpression in permethrin resistant mosquitoes suggested the importance of co-overexpression of multiple P450 genes with their obligatory electron donor CPR in the complex detoxification system, boosting the metabolism of permethrin and hence the development of permethrin resistance in Cx. quinquefasciatus.

scholarly journals Failure of Permethrin-Treated Military Uniforms to Protect Against a Laboratory-Maintained Knockdown-Resistant Strain of Aedes aegypti

2020 ◽  
Vol 36 (2) ◽  
pp. 127-130
Author(s):  
Alden S. Estep ◽  
Neil D. Sanscrainte ◽  
Ingeborg Cuba ◽  
Gregory M. Allen ◽  
James J. Becnel ◽  
...  
Keyword(s):  
Puerto Rico ◽  
Aedes Aegypti ◽  
Resistant Strain ◽  
Untreated Control ◽  
Pyrethroid Resistance ◽  
Disease Vectors ◽  
Significant Protection ◽  
Additional Testing ◽  
Resistant Strains ◽  
Preliminary Study

ABSTRACT Military forces and the recreational industry rely on the repellent properties of permethrin-treated fabrics and N,N-diethyl-meta-toluamide (deet)–based lotions to provide protection from disease vectors and hematophagous organisms. Concerns regarding efficacy have been raised as pyrethroid resistance becomes more common and recent publications present contradictory conclusions. In this preliminary study, consenting volunteers were exposed to pyrethroid-susceptible and pyrethroid-resistant Aedes aegypti strains while wearing sleeves of untreated or permethrin-treated army uniform fabric as well as with untreated or deet-treated exposed forearms. Deet was nearly 100% effective against both susceptible and resistant strains. However, permethrin treatment provided no significant protection against the resistant Puerto Rico strain relative to untreated control sleeves. These results confirm that pyrethroid-resistant vectors can negate the efficacy of permethrin-treated uniforms. Additional testing with resistant field strains is needed to better understand the risk to service members.

scholarly journals Flight take-off and walking behavior of insecticide-susceptible and – resistant strains of Sitophilus zeamais exposed to deltamethrin

2009 ◽  
Vol 99 (4) ◽  
pp. 393-400 ◽  
Author(s):  
N.M.P. Guedes ◽  
R.N.C. Guedes ◽  
G.H. Ferreira ◽  
L.B. Silva
Keyword(s):  
Resistant Strain ◽  
Insect Pests ◽  
Behavioral Responses ◽  
Insect Behavior ◽  
Sitophilus Zeamais ◽  
Maize Weevil ◽  
Walking Behavior ◽  
Resistant Strains ◽  
Managed Ecosystems ◽  
Behavioral Resistance

AbstractInsects have evolved a variety of physiological and behavioral responses to various toxins in natural and managed ecosystems. However, insect behavior is seldom considered in insecticide studies although insects are capable of changing their behavior in response to their sensory perception of insecticides, which may compromise insecticide efficacy. This is particularly serious for insect pests that are physiologically resistant to insecticides since insecticide avoidance may further compromise their management. Locomotion plays a major role determining insecticide exposure and was, therefore, considered in investigating the behavioral responses of male and female adult insects from an insecticide-susceptible and two insecticide-resistant strains of the maize weevil Sitophilus zeamais Motschulsky (Coleoptera: Curculionidae), a major pest of stored cereals. Different dose-dependent behavioral responses were expected among strains with behavioral resistance less likely to occur in physiologically resistant insects since they are able to withstand higher doses of insecticide. The behavioral responses to deltamethrin-sprayed surfaces differed among the maize weevil strains. Such responses were concentration-independent for all of the strains. Stimulus-independent behavioral resistance was unrelated to physiological resistance with one resistant strain exhibiting higher rates of flight take-off and the other resistant strain exhibiting lower flight take-off. Female mobility was similar for all strains, unlike male mobility. Males of each strain exhibited a pattern of mobility following the same trend of flight take-off. Behavioral patterns of response to insecticide are, therefore, variable among strains, particularly among insecticide-resistant strains, and worth considering in resistance surveys and management programs.

Mechanisms of insecticide resistance in a temephos selected Culex quinquefasciatus (Diptera: Culicidae) strain from Sri Lanka

1990 ◽  
Vol 80 (4) ◽  
pp. 453-457 ◽  
Author(s):  
H.T.R. Peiris ◽  
J. Hemingway
Keyword(s):  
Cytochrome P450 ◽  
Sri Lanka ◽  
Culex Quinquefasciatus ◽  
Resistant Strain ◽  
Resistance Mechanism ◽  
Transferase Activity ◽  
Glutathione S Transferase ◽  
Biochemical Assays ◽  
Significant Difference ◽  
Naphthyl Acetate

AbstractCulex quinquefasciatus Say from Peliyagoda, Sri Lanka, has larval resistance to temephos, malathion, fenitrothion and chlorpyrifos. Biochemical assays on individual resistant and susceptible mosquitoes of this strain showed that there was a good correlation between this resistance and increased esterase activity with both 1-and 2-naphthyl acetate, which appears to be the major resistance mechanism in this multiple organophosphate resistant strain. There was no significant difference in malaoxon, bendiocarb or propoxur sensitivity of the acetylcholinesterase from the resistant and susceptible strains, indicating that the sensitivity of the target site has not been altered. Biochemical assays on mass homogenates of the resistant and susceptible strains showed no correlation between resistance and the level of glutathione s-transferase activity, or the amount of cytochrome P450 present.

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