Further studies on the use of chicken embryo infections for the study of drug resistance in Eimeria tenella

Parasitology ◽  
1976 ◽  
Vol 73 (3) ◽  
pp. 275-282 ◽  
Author(s):  
H. D. Chapman
Keyword(s):  
Drug Resistance ◽  
Drug Concentration ◽  
Chicken Embryo ◽  
The Other ◽  
Cross Resistance ◽  
Drug Resistant ◽  
Mutagenic Agent ◽  
Development Of Resistance ◽  
Drug Concentrations ◽  
Resistant Lines

Infections in the chicken embryo have been used to study the development of drug resistance in an embryo adapted strain of E. tenella. Resistance was developed to decoquinate, clopidol and robenidine by serially passaging this strain, but evidence for the development of resistance to amprolium was inconclusive. Resistance to decoquinate developed more readily than to the other drugs. Attempts to increase resistance to clopidol, robenidine and amprolium by increasing the sporozoite inoculum and by the use of a mutagenic agent were unsuccesful. No cross-resistance was found between the 4 drugs.Drug resistant lines of the Houghton strain (H) of E. tenella, made resistant to the 4 anticoccidial drugs by passage in chickens, were found to be resistant when evaluated using chicken embryo infections. Lines made resistant to decoquinate were not controlled by any concentration of this drug, suggesting that resistance, once developed, was absolute and not dependent on drug concentration. Lines made resistant to robenidine, clopidol and amprolium, however, were controlled by higher drug concentrations suggesting that in this case resistance was dependent on drug concentration.

DDRE-27. METABOLIC SWITCHING AS A MECHANISM OF DRUG RESISTANCE AGAINST NAMPT INHIBITION IN GLIOMAS

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi80-vi80
Author(s):  
Pratibha Sharma ◽  
Vinay Puduvalli
Keyword(s):  
Drug Resistance ◽  
Energy Metabolism ◽  
Cross Reactivity ◽  
Alternative Methods ◽  
Cross Resistance ◽  
Significant Heterogeneity ◽  
Drug Resistant ◽  
High Accumulation ◽  
Metabolic Switch ◽  
Nicotinamide Phosphoribosyltransferase

Abstract BACKGROUND Gliomas exhibit significant heterogeneity in treatment response and characteristically deploy resistance mechanisms that render conventional therapies ineffective. Recently, novel agents have been developed that target regulators of differential energy pathways specifically utilized by gliomas. We previously reported on the targeting of Nicotinamide Phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the NAD+ salvage pathway and its essential role in glioma cell energy metabolism. Here, we determined the mechanisms by which glioma cells bypass blockade of energy metabolism and develop resistance to NAMPT inhibitors. METHODS Using isogenic parental and drug-resistant patient-derived glioma stem-like cells (GSCs), we examined adaptive changes after NAMPT inhibition in glycolysis, mitochondrial function (oxidative state, basal respiration rate, spare respiratory capacity, maximum respiration capacity and proton leak) and metabolite levels using Agilent Seahorse assay and targeted metabolomics. Cross reactivity across various NAMPT inhibitors was measured using Cell Titer Glo assay. RESULTS GSCs exposed for an extended period to sub-lethal doses of FK866, a potent NAMPT inhibitor, acquired drug resistance to the agent which were also cross-resistant to other NAMPT inhibitors. Drug-resistant GSCs showed a decrease in extracellular acidification rate and oxygen consumption rate compared to isogenic parental lines. Further, metabolomic analysis showed a high accumulation of glutamate, creatine and histidine metabolites in these cells. These results indicate a shift in metabolism of drug-resistant GSCs from carbon metabolism to nitrogen metabolism. CONCLUSIONS GSCs resistant to the NAMPT inhibitor, FK866 showed cross resistance to other NAMPT inhibitors indicating specificity of this effect. The resistance mechanism involves a shift of preferential energy generation from glycolysis to amino acid metabolism which allows the cells to use alternative methods to generate NAD. Additional results from ongoing studies to delineate the mechanisms of metabolic switch in the drug resistance lines will be presented that will help develop strategies to combat resistance to NAMPT inhibitors.

The development of resistance to metachloridine inPlasmodium gallinaceumin Chicks

Parasitology ◽  
1953 ◽  
Vol 42 (3-4) ◽  
pp. 277-286 ◽  
Author(s):  
Ann Bishop ◽  
Elspeth W. McConnachie
Keyword(s):  
Growth Rate ◽  
Drug Resistance ◽  
Normal Population ◽  
Rapid Development ◽  
Cross Resistance ◽  
Development Of Resistance ◽  
The Gift ◽  
Higher Doses ◽  
Resistance Tests ◽  
Selection Of

1. An increase in resistance to metachloridine of more than 100-fold was obtained within a few weeks in a strain ofPlasmodium gallinaceumtreated with gradually increasing doses of the drug and maintained in young chicks by blood-inoculation at intervals of 2–3 days.2. There was no evidence that the rapid development of resistance arose by the selection of highly resistant individuals present in the normal population.3. Two strains ofP. gallinaceumpassaged through chicks treated with 0·025 mg. doses of the drug gradually became resistant to greater concentrations than that to which they had been exposed, though their growth rate decreased when they were inoculated into birds receiving higher doses of the drug.4. In both strains maintained in birds treated with 0·025 mg. doses of the drug, resistance reached a maximum beyond which it did not increase.5. Cross-resistance tests failed to show any relationship in mode of action between meta-chloridine and pamaquin, mepacrine, quinine or chloroquine. A strain ofP. gallinaceum, highly resistant to metachloridine, showed slight resistance to sulphadiazine, sulphapyridine and sulphathiazole, but none to sulphanilamide or proguanil.We are indebted to the Cyanamid Products Ltd., London, for the gift of the Folvite used in these experiments.

scholarly journals Role of embB Codon 306 Mutations in Mycobacterium tuberculosis Revisited: a Novel Association with Broad Drug Resistance and IS6110 Clustering Rather than Ethambutol Resistance

2005 ◽  
Vol 49 (9) ◽  
pp. 3794-3802 ◽  
Author(s):  
Manzour Hernando Hazbón ◽  
Miriam Bobadilla del Valle ◽  
Marta Inírida Guerrero ◽  
Mandira Varma-Basil ◽  
Ingrid Filliol ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Mycobacterium Tuberculosis ◽  
Odds Ratio ◽  
Univariate Analysis ◽  
Drug Susceptibility ◽  
Drug Resistant ◽  
Development Of Resistance ◽  
Resistance Patterns ◽  
Novel Association

ABSTRACT Mutations at position 306 of embB (embB306) have been proposed as a marker for ethambutol resistance in Mycobacterium tuberculosis; however, recent reports of embB306 mutations in ethambutol-susceptible isolates caused us to question the biological role of this mutation. We tested 1,020 clinical M. tuberculosis isolates with different drug susceptibility patterns and of different geographical origins for associations between embB306 mutations, drug resistance patterns, and major genetic group. One hundred isolates (10%) contained a mutation in embB306; however, only 55 of these mutants were ethambutol resistant. Mutations in embB306 could not be uniquely associated with any particular type of drug resistance and were found in all three major genetic groups. A striking association was observed between these mutations and resistance to any drug (P < 0.001), and the association between embB306 mutations and resistance to increasing numbers of drugs was highly significant (P < 0.001 for trend). We examined the association between embB306 mutations and IS6110 clustering (as a proxy for transmission) among all drug-resistant isolates. Mutations in embB306 were significantly associated with clustering by univariate analysis (odds ratio, 2.44; P = 0.004). In a multivariate model that also included mutations in katG315, katG463, gyrA95, and kasA269, only mutations in embB306 (odds ratio, 2.14; P = 0.008) and katG315 (odds ratio, 1.99; P = 0.015) were found to be independently associated with clustering. In conclusion, embB306 mutations do not cause classical ethambutol resistance but may predispose M. tuberculosis isolates to the development of resistance to increasing numbers of antibiotics and may increase the ability of drug-resistant isolates to be transmitted between subjects.

Eimeria tenella in chickens: development of resistance to quinolone anticoccidial drugs

Parasitology ◽  
1975 ◽  
Vol 71 (1) ◽  
pp. 41-49 ◽  
Author(s):  
H. D. Chapman
Keyword(s):  
Drug Resistance ◽  
Weight Gain ◽  
Liquid Nitrogen ◽  
Selection Pressure ◽  
Drug Tolerance ◽  
Eimeria Tenella ◽  
Cross Resistance ◽  
Drug Selection ◽  
Laboratory Conditions ◽  
Development Of Resistance

The development of drug resistance by the present Houghton strain of Eimeria tenella to the quinolones, methyl benzoquate and buquinolate, was found to take place after a single experimental passage. The development of resistance was independent of drug selection pressure and showed cross resistance to other quinolones, but not to amprolium and robenidine. When the Weybridge, Beltsville and Elberfeld strains of E. tenella were compared under similar laboratory conditions, the Weybridge and Elberfeld strains developed resistance to methyl benzoquate after 6 passages and the Beltsville after 5. Studies on the response of the Houghton strain to methyl benzoquate and buquinolate revealed that the drugs did not completely control the infection as measured by weight gain and that oocyst production was not suppressed. These observations indicate that the strain had already acquired some resistance to these drugs. This was confirmed by examining the resistance to methyl benzoquate of a culture of the Houghton strain of E. tenella which had been stored frozen in liquid nitrogen since 1969. This showed full sensitivity to the drug and developed resistance after 8 passages. This suggests that drug tolerance has been acquired by the Houghton strain since 1969.Oocyst lines were established from the Houghton strain by infecting single birds with approximately 10 oocysts. Eleven of these lines were found to be sensitive to methyl benzoquate, and nine to give rise to resistant parasites. It is concluded that the Houghton strain is contaminated by a small number of resistant oocysts which can be eliminated from a culture by dilution of the challenge inoculum. One of these Houghton oocyst lines, sensitive to methyl benzoquate, developed resistance after 8 serial passages.

Transferred drug-resistance in Eimeria maxima

Parasitology ◽  
1975 ◽  
Vol 71 (3) ◽  
pp. 385-392 ◽  
Author(s):  
L. P. Joyner ◽  
C. C. Norton
Keyword(s):  
Drug Resistance ◽  
The Other ◽  
Drug Resistant ◽  
Resistance Factors ◽  
Eimeria Maxima ◽  
Series Of Experiments ◽  
Resistant Strains ◽  
Drug Resistant Strains

A series of experiments is described in which two drug-resistant strains of Eimeria maxima were passaged together in untreated chicks. The resultant oocysts were then inoculated into chicks treated with both drugs. When strains resistant to methyl benzoquate and sulphaquinoxaline or clopidol and sulphaquinoxaline were used the resultant infections were not controlled by the double treatment, indicating the acquisition of resistance factors by one strain from the other. When strains resistant to clopidol and methyl benzoquate were used the phenomenon was not observed.

scholarly journals Opportunities for Overcoming Mycobacterium tuberculosis Drug Resistance: Emerging Mycobacterial Targets and Host-Directed Therapy

2019 ◽  
Vol 20 (12) ◽  
pp. 2868 ◽  
Author(s):  
Eveline Torfs ◽  
Tatiana Piller ◽  
Paul Cos ◽  
Davie Cappoen
Keyword(s):  
Drug Resistance ◽  
Mycobacterium Tuberculosis ◽  
Antibiotic Susceptibility ◽  
Treatment Options ◽  
The Other ◽  
Adjunctive Treatment ◽  
Lung Pathology ◽  
Drug Resistant ◽  
Novel Treatment ◽  
Novel Targets

The ever-increasing incidence of drug-resistant Mycobacterium tuberculosis infections has invigorated the focus on the discovery and development of novel treatment options. The discovery and investigation of essential mycobacterial targets is of utmost importance. In addition to the discovery of novel targets, focusing on non-lethal pathways and the use of host-directed therapies has gained interest. These adjunctive treatment options could not only lead to increased antibiotic susceptibility of Mycobacterium tuberculosis, but also have the potential to avoid the emergence of drug resistance. Host-directed therapies, on the other hand, can also reduce the associated lung pathology and improve disease outcome. This review will provide an outline of recent opportunities.

scholarly journals Multidrug-resistant phenotype cosegregates with an amplified gene in somatic cell hybrids of drug-resistant Chinese hamster ovary cells and drug-sensitive murine cells.

1986 ◽  
Vol 6 (12) ◽  
pp. 4268-4273 ◽  
Author(s):  
L D Teeter ◽  
J A Sanford ◽  
S Sen ◽  
R L Stallings ◽  
M J Siciliano ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Somatic Cell ◽  
Chinese Hamster Ovary ◽  
Cho Cells ◽  
Chinese Hamster ◽  
Cross Resistance ◽  
Drug Resistant ◽  
Somatic Cell Hybrids ◽  
Cell Hybrids ◽  
Primary Drug Resistance

Gene amplification has been associated with multidrug resistance (MDR) in several drug-resistant Chinese hamster ovary (CHO) cell lines which exhibit cross-resistance to other unrelated, cytotoxic drugs. In situ hybridization studies (Teeter et al., J. Cell Biol., in press) suggested the presence of an amplified gene associated with the MDR phenotype on the long arm of either of the largest CHO chromosomes (1 or Z1) in vincristine-resistant cells. In this study, somatic cell hybrids were constructed between these vincristine-resistant CHO cells and drug-sensitive murine cells to determine the functional relationship between the chromosome bearing the amplified sequences and the MDR phenotype. Hybrids exhibited primary drug resistance and MDR in an incomplete dominant fashion. Hybrid clones and subclones segregated CHO chromosomes. Concordant segregation between vincristine resistance, the MDR phenotype, the presence of the MDR-associated amplified sequences, overexpression of the gene located in those sequences, and CHO chromosome Z1 was consistent with the hypothesis that there is an amplified gene on chromosome Z1 of the vincristine-resistant CHO cells which is responsible for the MDR in these cells. A low level of discordance between CHO chromosomes Z8 and 2 and the drug resistance phenotype suggests that these chromosomes may contain genes involved with the MDR phenotype.

scholarly journals Antibiotic interactions shape short-term evolution of resistance in E. faecalis

2019 ◽  
Author(s):  
Ziah Dean ◽  
Jeff Maltas ◽  
Kevin B. Wood
Keyword(s):  
Drug Resistance ◽  
Bacterial Infections ◽  
Response Surfaces ◽  
Drug Combinations ◽  
Cross Resistance ◽  
Multi Drug Resistance ◽  
Trade Offs ◽  
Drug Concentrations ◽  
Wide Range ◽  
Growth Adaptation

ABSTRACTAntibiotic combinations are increasingly used to combat bacterial infections. Multidrug therapies are a particularly important treatment option for E. faecalis, an opportunistic pathogen that contributes to high-inoculum infections such as infective endocarditis. While numerous synergistic drug combinations for E. faecalis have been identified, much less is known about how different combinations impact the rate of resistance evolution. In this work, we use high-throughput laboratory evolution experiments to quantify adaptation in growth rate and drug resistance of E. faecalis exposed to drug combinations exhibiting different classes of interactions, ranging from synergistic to suppressive. We identify a wide range of evolutionary behavior, including both increased and decreased rates of growth adaptation, depending on the specific interplay between drug interaction and cross resistance. For example, selection in a dual-lactam combination leads to accelerated growth adaptation compared to selection with the individual drugs, even though the resulting resistance profiles are nearly identical. On the other hand, populations evolved in an aminoglycoside and -lactam combination exhibit decreased growth adaptation and resistant profiles that depend on the specific drug concentrations. We show that the main qualitative features of these evolutionary trajectories can be explained by simple rescaling arguments that correspond to geometric transformations of the two-drug growth response surfaces measured in ancestral cells. The analysis also reveals multiple examples where resistance profiles selected by drug combinations correspond to (nearly) optimized linear combinations of those selected by the component drugs. Our results highlight trade-offs between drug interactions and collateral effects during the evolution of multi-drug resistance and emphasize evolutionary benefits and disadvantages of particular drug pairs targeting enterococci.

scholarly journals The persistance of drug resistant Escherichia coli strains in the majority faecal flora of calves

1984 ◽  
Vol 93 (3) ◽  
pp. 547-557 ◽  
Author(s):  
M. Hinton ◽  
P. D. Rixson ◽  
Vivien Allen ◽  
A. H. Linton
Keyword(s):  
Escherichia Coli ◽  
Drug Resistance ◽  
Resistance Index ◽  
The Other ◽  
Antibacterial Drug ◽  
Drug Resistant ◽  
Faecal Flora ◽  
Resistance Determinants ◽  
Veterinary School ◽  
Antibacterial Drug Resistance

SummaryTwo groups of calves, one of three and the other of two animals, were purchased in markets and reared initially on a commercial veal unit for 1 month and 4 months respectively. They were then moved to the Veterinary School, Langford, and kept for a further 6 and 4 months respectively. The animals were sampled weekly and a continual turnover in the strains forming the majority Escherichia coli faecal flora was demonstrated for all calves. Antibacterial-drug resistance, as measured by an Antibiotic Resistance Index (ARI), increased after arrival on the veal unit and persisted at high levels during the whole of their stay. After moving to Langford the ARI fell. Initially there was a reduction in the average number of resistance determinants per resistant strain and then, after a delay of up to 8 weeks, by an increase in the proportion of isolates that were fully sensitive. The source of the sensitive strains was not ascertained, although their appearance was not associated specifically with either weaning or turning out to pasture.

scholarly journals MycoResistance: a curated resource of drug resistance molecules in Mycobacteria

Database ◽  
2019 ◽  
Vol 2019 ◽  
Author(s):  
Enyu Dai ◽  
Hao Zhang ◽  
Xu Zhou ◽  
Qian Song ◽  
Di Li ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Molecular Mechanisms ◽  
Cross Resistance ◽  
Drug Resistant ◽  
Genetic Determinants ◽  
Related Information ◽  
Precise Diagnosis ◽  
Global Concern ◽  
User Friendly ◽  
Extensively Drug Resistance

Abstract The emergence and spread of drug-resistant Mycobacterium tuberculosis is of global concern. To improve the understanding of drug resistance in Mycobacteria, numerous studies have been performed to discover diagnostic markers and genetic determinants associated with resistance to anti-tuberculosis drug. However, the related information is scattered in a massive body of literature, which is inconvenient for researchers to investigate the molecular mechanism of drug resistance. Therefore, we manually collected 1707 curated associations between 73 compounds and 132 molecules (including coding genes and non-coding RNAs) in 6 mycobacterial species from 465 studies. The experimental details of molecular epidemiology and mechanism exploration research were also summarized and recorded in our work. In addition, multidrug resistance and extensively drug resistance molecules were also extracted to interpret the molecular mechanisms that are responsible for cross resistance among anti-tuberculosis drugs. Finally, we constructed an omnibus repository named MycoResistance, a user friendly interface to conveniently browse, search and download all related entries. We hope that this elaborate database will serve as a beneficial resource for mechanism explanations, precise diagnosis and effective treatment of drug-resistant mycobacterial strains.

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