scholarly journals Drug resistance in protozoan parasites

2017 ◽  
Vol 1 (6) ◽  
pp. 627-632 ◽  
Author(s):  
Harry P. de Koning
Keyword(s):  
Drug Resistance ◽  
Cross Resistance ◽  
Protozoan Parasites ◽  
Two Factors

As with all other anti-infectives (antibiotics, anti-viral drugs, and anthelminthics), the limited arsenal of anti-protozoal drugs is being depleted by a combination of two factors: increasing drug resistance and the failure to replace old and often shamefully inadequate drugs, including those compromised by (cross)-resistance, through the development of new anti-parasitics. Both factors are equally to blame: a leaking bathtub may have plenty of water if the tap is left open; if not, it will soon be empty. Here, I will reflect on the factors that contribute to the drug resistance emergency that is unfolding around us, specifically resistance in protozoan parasites.

scholarly journals An Overview of Drug Resistance in Protozoal Diseases

2019 ◽  
Vol 20 (22) ◽  
pp. 5748 ◽  
Author(s):  
Capela ◽  
Moreira ◽  
Lopes
Keyword(s):  
Drug Resistance ◽  
Health Problem ◽  
Mechanisms Of Action ◽  
New Drugs ◽  
Cross Resistance ◽  
Protozoan Parasites ◽  
Economic Health

Protozoan diseases continue to be a worldwide social and economic health problem. Increased drug resistance, emerging cross resistance, and lack of new drugs with novel mechanisms of action significantly reduce the effectiveness of current antiprotozoal therapies. While drug resistance associated to anti-infective agents is a reality, society seems to remain unaware of its proportions and consequences. Parasites usually develops ingenious and innovative mechanisms to achieve drug resistance, which requires more research and investment to fight it. In this review, drug resistance developed by protozoan parasites Plasmodium, Leishmania, and Trypanosoma will be discussed.

Impact of genotypic diversity on selection of subtype-specific drug resistance profiles during raltegravir-based therapy in individuals infected with B and BF recombinant HIV-1 strains

2020 ◽  
Vol 75 (6) ◽  
pp. 1567-1574
Author(s):  
Daniela Sánchez ◽  
Solange Arazi Caillaud ◽  
Ines Zapiola ◽  
Silvina Fernandez Giuliano ◽  
Rosa Bologna ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Current Knowledge ◽  
Phylogenetic Analyses ◽  
Genotypic Diversity ◽  
Resistance Testing ◽  
Cross Resistance ◽  
Resistance Mutations ◽  
Middle Income ◽  
Subtype B ◽  
Hiv 1

Abstract Background Current knowledge on HIV-1 resistance to integrase inhibitors (INIs) is based mostly on subtype B strains. This contrasts with the increasing use of INIs in low- and middle-income countries, where non-B subtypes predominate. Materials and methods HIV-1 drug resistance genotyping was performed in 30 HIV-1-infected individuals undergoing virological failure to raltegravir. Drug resistance mutations (DRMs) and HIV-1 subtype were characterized using Stanford HIVdb and phylogenetic analyses. Results Of the 30 integrase (IN) sequences, 14 were characterized as subtype F (47%), 8 as subtype B (27%), 7 as BF recombinants (23%) and 1 as a putative CRF05_DF (3%). In 25 cases (83%), protease and reverse transcriptase (PR-RT) sequences from the same individuals confirmed the presence of different BF recombinants. Stanford HIVdb genotyping was concordant with phylogenetic inference in 70% of IN and 60% of PR-RT sequences. INI DRMs differed between B and F IN subtypes, with Q148K/R/H, G140S and E138K/A being more prevalent in subtype B (63% versus 0%, P = 0.0021; 50% versus 0%, P = 0.0096; and 50% versus 0%, P = 0.0096, respectively). These differences were independent of the time on raltegravir therapy or viral load at the time of genotyping. INI DRMs in subtype F IN genomes predicted a lower level of resistance to raltegravir and no cross-resistance to second-generation INIs. Conclusions Alternative resistance pathways to raltegravir develop in subtypes B and F IN genomes, with implications for clinical practice. Evaluating the role of HIV-1 subtype in development and persistence of mutations that confer resistance to INIs will be important to improve algorithms for resistance testing and optimize the use of INIs.

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.

Electrophoretic analysis of 248 clinical breast cancer specimens for P-glycoprotein overexpression or gene amplification.

1989 ◽  
Vol 7 (8) ◽  
pp. 1129-1136 ◽  
Author(s):  
D E Merkel ◽  
S A Fuqua ◽  
A K Tandon ◽  
S M Hill ◽  
A U Buzdar ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Gene Amplification ◽  
Multiple Drug Resistance ◽  
Electrophoretic Analysis ◽  
Gene Copy ◽  
Cross Resistance ◽  
Glycoprotein Gene ◽  
P Glycoprotein ◽  
Clinical Breast

Multiple drug resistance (MDR), consisting of acquired cross resistance to anthracyclines, vinca alkyloids, and other antineoplastic antibiotics, has been described in a variety of cell lines. This MDR phenotype is associated with overexpression and sometimes amplification of a gene coding for a 170 kDa glycoprotein, termed P-glycoprotein. To understand the role of this mechanism in clinical breast cancer, 248 breast cancer specimens representing both untreated primary and refractory relapsing disease were probed for evidence of P-glycoprotein gene amplification or overexpression using Southern, Northern, or Western blot techniques. In no case was an increase in P-glycoprotein gene copy number or expression detected. Though these findings do not necessarily rule out a role for P-glycoprotein in mediating drug resistance in breast cancer, electrophoretic analysis of clinical specimens is unlikely to provide useful predictive information. More sensitive assays must be developed to overcome the difficulties inherent in analyzing heterogenous tissue samples.

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 Resistance in Patients Failing Integrase Strand Transfer Inhibitors: A Call to Replace Raltegravir With Dolutegravir in Third-Line Treatment in South Africa

2019 ◽  
Vol 6 (10) ◽  
Author(s):  
Kim Steegen ◽  
Gert Van Zyl ◽  
Esrom Letsoalo ◽  
Mathilda Claassen ◽  
Lucia Hans ◽  
...  
Keyword(s):  
South Africa ◽  
Drug Resistance ◽  
Cross Resistance ◽  
Strand Transfer ◽  
Line Treatment ◽  
Middle Income ◽  
Integrase Strand Transfer Inhibitors ◽  
Resistance Patterns ◽  
Third Line ◽  
Third Line Treatment

Abstract Data on integrase resistance patterns in low- and middle-income countries (LMICs) is scarce. We assessed genotypic drug resistance in 43 patients with virological failure on integrase strand transfer inhibitors (INSTIs) containing regimens as part of the third-line treatment program in South Africa. Of the raltegravir (RAL)-exposed patients 20 of 34 (59%) had ≥1 major INSTI mutation, including 2 (6%) with dolutegravir (DTG) cross-resistance. Dolutegravir resistance was detected in 1 of 4 DTG-exposed patients. Replacing RAL with DTG may reduce the risk of INSTI mutations. We recommend DTG drug resistance monitoring when DTG is introduced at a larger scale in LMICs.

Prevalence of drug resistance genotypes causing broad cross-resistance to nucleos(t)ide analogues

AIDS ◽  
2004 ◽  
Vol 18 (4) ◽  
pp. 689-690 ◽  
Author(s):  
Oscar Gallego ◽  
Carmen de Mendoza ◽  
Angélica Corral ◽  
Vincent Soriano
Keyword(s):  
Drug Resistance ◽  
Cross Resistance

DRUG RESISTANCE AND MEMBRANE ALTERATION IN MUTANTS OF MAMMALIAN CELLS

1975 ◽  
Vol 17 (4) ◽  
pp. 503-515 ◽  
Author(s):  
Victor Ling
Keyword(s):  
Drug Resistance ◽  
Mammalian Cells ◽  
Molecular Conformation ◽  
Membrane Lipids ◽  
Chinese Hamster Ovary Cells ◽  
Mutant Cell ◽  
Chinese Hamster ◽  
Cross Resistance ◽  
Permeability Barrier ◽  
Colchicine Resistance

Independent colchicine-resistant (CHR) mutants of Chinese hamster ovary cells displaying reduced permeability to colchicine have been isolated. A distinguishing feature of these membrane-altered mutants is their pleiotropic cross-resistance to a variety of unrelated compounds. Genetic characterization of the CHR lines indicates that colchicine resistance and cross-resistance to other drugs are of a dominant nature in somatic cell hybrids. Revertants of CHR have been isolated which display decreased resistance to colchicine and a corresponding decrease in resistance to other drugs. These results strongly suggest that colchicine resistance and the pleiotropic cross-resistance are the result of the same mutation(s). Biochemical studies indicate that although colchicine is transported into our cells by passive diffusion, no major alterations in the membrane lipids could be detected in mutant cells. However, there appears to be an energy-dependent process in these cells which actively maintains a permeability barrier against colchicine and other drugs. The CHR cells might be altered in this process. A new glycoprotein has been identified in mutant cell membranes which is not present in parental cells, and is greatly reduced in revertant cells. A model for colchicine-resistance is proposed which suggests that certain membrane proteins such as the new glycoprotein of CHR cells, are modulators of membrane fluidity (mmf proteins) whose molecular conformation regulates membrane permeability to a variety of compounds and that the CHR mutants are altered in their mmf proteins. The possible importance of the CHR cells as models for investigating aspects of chemotherapy related to drug resistance is discussed.

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