scholarly journals MODERN ETHIOTROPIC CHEMOTHERAPY OF HUMAN CYTOMEGALOVIRUS INFECTION: CLINICAL EFFECTIVENESS, MOLECULAR MECHANISM OF ACTION, DRUG RESISTANCE, NEW TRENDS AND PROSPECTS. PART 2

2018 ◽  
Vol 63 (6) ◽  
pp. 250-260
Author(s):  
V. L. Andronova
Keyword(s):  
Drug Resistance ◽  
Human Cytomegalovirus ◽  
Clinical Effectiveness ◽  
Great Activity ◽  
Third Phase ◽  
Viral Cyclin ◽  
Preclinical Trials ◽  
Molecular Mechanism Of Action ◽  
Resistant Strains ◽  
Human Cmv

A number of synthetic compounds, such as the nucleoside analog ganciclovir, its L-valine ester (a metabolic precursor of ganciclovir) and pyrophosphate analog foscarnet, are permitted for the treatment of HCMV-related diseases in the WHO European Region. The viral DNA- polymerase is used by all these drugs as a bio-target. However, the usage of standard anti-CMV therapy is accompanied by severe side effects, as well as the development of drug resistance in the virus, mainly in conditions of immunodeficiency. In this review, we focused on viral proteins of interest as new potential targets and their inhibitors, such as the inhibitor of human CMV terminology, lethermovir, which showed great activity in the third phase of clinical trials, inhibitors of viral cyclin-dependent kinase (maribavir, cyclopropavir ) and a number of compounds exhibiting anti-HCMV-activity, undergoing only preclinical trials in the experiment. Inclusion of new anti-CMV agents that are active against GСV/PFA/CDV-resistant strains of CMV into standard prophylactic and therapeutic regimens, will allow to increase the effectiveness of anti-CMV therapy, including in cases when standard therapy is ineffective. Areas covered: the international databases such as A MEDLINE, PubMed, eLIBRARY.RU, ClinicalTrials.gov., etc. with the purpose of obtaining information on compounds showing selective action against the human cytomegalovirus, the most promising for the development of drugs.

scholarly journals MODERN ETHIOTROPIC CHEMOTHERAPY OF HUMAN CYTOMEGALOVIRUS INFECTION: CLINICAL EFFECTIVENESS, MOLECULAR MECHANISM OF ACTION, DRUG RESISTANCE, NEW TRENDS AND PROSPECTS. PART 1

2018 ◽  
Vol 63 (5) ◽  
pp. 202-211
Author(s):  
V. L. Andronova
Keyword(s):  
Drug Resistance ◽  
Dna Polymerase ◽  
Antiviral Agents ◽  
Clinical Effectiveness ◽  
Structural Features ◽  
Modified Nucleosides ◽  
Second Line ◽  
Molecular Mechanism Of Action ◽  
Human Cytomegalovirus Infection ◽  
New Compounds

Modern chemotherapy of cytomegalovirus (CMV) infections has a very limited arsenal of first-line drugs. These are preparations of ganciclovir (GCV) belonging to the class of modified nucleosides and its metabolic precursor ganciclovir valine ester. After three-step phosphorylation, GCV, as a structural analogue of the natural nucleotide, competes with it for binding to DNA polymerase and, due to its structural features, inhibits its activity. However, with prolonged use of GCV, mainly under conditions of immunosuppression, the virus develops drug resistance associated in most cases with changes in pUL97 catalyzing the first stage of GCV phosphorylation, as well as in the catalytic subunit of DNA polymerase. When variants of viruses resistant to GCV appear, second-line drugs are used: pyrophosphate analog of foscarnet and nucleotide cidofovir. Resistance to second-line drugs is due to mutations in the pol-gene and in a number of cases leads to multiresistance, which makes it impossible to use traditional anti-CMV drugs. In addition, the use of all of the above drugs is accompanied by the development of severe side effects. All of the above determines the need to search for new compounds that can effectively inhibit the reproduction of the virus, harmless to the macroorganism, convenient to use, overcoming the drug resistance barrier in viruses. As a result of the search in international databases (PubMed, MedLine, eLIBRARY.RU, ClinicalTrials.gov, etc.), the main trends in the search for new anti-CMV agents were identified. In the first part of the review, we concentrated on compounds that are modifications of known antiviral agents currently used in clinical practice, the most promising for the development of drug anti-CMV drugs.

Detecting human cytomegalovirus drug resistant mutations and monitoring the emergence of resistant strains using real-time PCR

2014 ◽  
Vol 61 (2) ◽  
pp. 270-274 ◽  
Author(s):  
Pavlina Volfova ◽  
Martina Lengerova ◽  
Jana Lochmanova ◽  
Dana Dvorakova ◽  
Dita Ricna ◽  
...  
Keyword(s):  
Real Time ◽  
Human Cytomegalovirus ◽  
Real Time Pcr ◽  
Drug Resistant ◽  
Resistant Strains

scholarly journals Constraints of Drug Resistance in Mycobacterium tuberculosis - Prospects for Pharmacological Reversion of Susceptibility to Antibiotics

2017 ◽  
Vol 8 (1) ◽  
pp. 33-43 ◽  
Author(s):  
Aleksandr I. Ilin ◽  
Murat E. Kulmanov ◽  
Ilya S. Korotetskiy ◽  
Marina V. Lankina ◽  
Gulshara K. Akhmetova ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Drug Resistance ◽  
Mycobacterium Tuberculosis ◽  
Genetic Heterogeneity ◽  
Multidrug Resistant ◽  
Resistance Mutations ◽  
General Increase ◽  
Drug Induced ◽  
Mdr Tb ◽  
Resistant Strains

Emergence of multidrug resistant strains ofMycobacterium tuberculosis(MDR-TB) threatens humanity. This problem was complicated by the crisis in development of new anti-tuberculosis antibiotics. Induced reversion of drug resistance seems promising to overcome the problem. Successful clinical trial of a new anti-tuberculosis nanomolecular complex FS-1 has demonstrated prospectively of this approach in combating MDR-TB. Several clinical MDR-TB cultures were isolated from sputum samples prior and in the process of the clinical trial. Every isolate was tested for susceptibility to antibiotics and then they were sequenced for comparative genomics. It was found that the treatment with FS-1 caused an increase in the number of antibiotic susceptible strains among Mtb isolates that was associated with a general increase of genetic heterogeneity of the isolates. Observed impairing of phthiocerol dimycocerosate biosynthesis by disruptive mutations inppsACDsubunits indicated a possible virulence remission for the sake of persistence. It was hypothesized that the FS-1 treatment eradicated the most drug resistant Mtb variants from the population by aggravating the fitness cost of drug resistance mutations. Analysis of distribution of these mutations in the global Mtb population revealed that many of them were incompatible with each other and dependent on allelic states of many other polymorphic loci. The latter discovery may explain the negative correlation between the genetic heterogeneity of the population and the level of drug tolerance. To the best of our knowledge, this work was the first experimental confirmation of the drug induced antibiotic resistance reversion by the induced synergy mechanism that previously was predicted theoretically.

A Mass Spectrometry-based Method to Detect Antiviral Drug Resistance in Human Cytomegalovirus

2009 ◽  
Vol 82 (2) ◽  
pp. A51
Author(s):  
Clara Posthuma ◽  
Martha Van der Beek ◽  
Caroline Van der Blij ◽  
Willy Spaan ◽  
Louis Kroes ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Drug Resistance ◽  
Human Cytomegalovirus ◽  
Antiviral Drug ◽  
Antiviral Drug Resistance

scholarly journals Drug Resistance Mechanisms ofMycoplasma pneumoniaeto Macrolide Antibiotics

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Xijie Liu ◽  
Yue Jiang ◽  
Xiaogeng Chen ◽  
Jing Li ◽  
Dawei Shi ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Resistance Mechanisms ◽  
23S Rrna ◽  
Macrolide Antibiotics ◽  
Rrna Gene ◽  
Site Mutation ◽  
23S Rrna Gene ◽  
Resistant Strains ◽  
Domain V ◽  
The 16S Rrna Gene

Throat swabs from children with suspectedMycoplasma pneumoniae(M. pneumoniae) infection were cultured for the presence ofM. pneumoniaeand its species specificity using the 16S rRNA gene. Seventy-sixM. pneumoniaestrains isolated from 580 swabs showed that 70 were erythromycin resistant with minimum inhibitory concentrations (MIC) around 32–512 mg/L. FiftyM. pneumoniaestrains (46 resistant, 4 sensitive) were tested for sensitivity to tetracycline, ciprofloxacin, and gentamicin. Tetracycline and ciprofloxacin had some effect, and gentamicin had an effect on the majority ofM. pneumoniaestrains. Domains II and V of the 23S rRNA gene and the ribosomal protein L4 and L22 genes, both of which are considered to be associated with macrolide resistance, were sequenced and the sequences were compared with the corresponding sequences in M129 registered with NCBI and the FH strain. The 70 resistant strains all showed a 2063 or 2064 site mutation in domain V of the 23S rRNA but no mutations in domain II. Site mutations of L4 or L22 can be observed in either resistant or sensitive strains, although it is not known whether this is associated with drug resistance.

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 Interstrain Variation in the Human Cytomegalovirus DNA Polymerase Sequence and Its Effect on Genotypic Diagnosis of Antiviral Drug Resistance

1999 ◽  
Vol 43 (6) ◽  
pp. 1500-1502 ◽  
Author(s):  
Sunwen Chou ◽  
Nell S. Lurain ◽  
Adriana Weinberg ◽  
Guang-Yung Cai ◽  
Prem L. Sharma ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Amino Acid ◽  
Dna Polymerase ◽  
Human Cytomegalovirus ◽  
Antiviral Drug ◽  
Resistance Mutations ◽  
Sequence Alignments ◽  
Coding Sequence ◽  
Antiviral Drug Resistance ◽  
Almost All

ABSTRACT The polymerase (pol) coding sequence was determined for 40 independent clinical cytomegalovirus isolates sensitive to ganciclovir and foscarnet. Sequence alignments showed >98% interstrain homology and amino acid variation in only 4% of the 1,237 codons. Almost all variation occurred outside of conserved functional domains where resistance mutations have been identified.

Drug-resistant human cytomegalovirus infection in children after allogeneic stem cell transplantation may have different clinical outcomes

Blood ◽  
2000 ◽  
Vol 96 (9) ◽  
pp. 3286-3289
Author(s):  
Tobias Eckle ◽  
Lothar Prix ◽  
Gerhard Jahn ◽  
Thomas Klingebiel ◽  
Rupert Handgretinger ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Human Cytomegalovirus ◽  
Allogeneic Stem Cell Transplantation ◽  
Hcmv Infection ◽  
Antiviral Drug ◽  
Increased Risk

Three seropositive pediatric recipients of allogeneic stem cell transplantation out of a group of 42 patients receiving T-cell–depleted, unrelated transplants and 37 patients receiving T-cell–depleted, haploidentical transplants were monitored longitudinally for human cytomegalovirus (HCMV) infection and the emergence of antiviral drug resistance. Early in the posttransplant course, all 3 patients developed HCMV mutations conferring drug resistance to ganciclovir. One child additionally developed multidrug resistance to foscarnet and cidofovir, with mutations in the viral phosphotransferase gene (UL97) and the DNA-polymerase gene (UL54) being found. These data show that resistant HCMV infection does not necessarily correlate with a severe clinical outcome. The early detection of genotypic resistance up to 129 days before the emergence of phenotypic resistance and the dissociation of resistance patterns among different body sites emphasize the importance of genotypic analyses of different DNA specimens for an efficient antiviral therapy. T-cell–depleted children having transplantation might be at an increased risk for the development of drug resistance.

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