scholarly journals A brief review on the mode of action of antinematodal drugs

2017 ◽  
Vol 67 (2) ◽  
pp. 137-152 ◽  
Author(s):  
Melanie Abongwa ◽  
Richard J. Martin ◽  
Alan P. Robertson
Keyword(s):  
Drug Resistance ◽  
Mode Of Action ◽  
Drug Targets ◽  
Parasite Species ◽  
Effective Control ◽  
Macrocyclic Lactones ◽  
Resistance Development ◽  
Cholinergic Agonists ◽  
Nematode Parasites ◽  
Parasite Populations

Abstract Anthelmintics are some of the most widely used drugs in veterinary medicine. Here we review the mechanism of action of these compounds on nematode parasites. Included are the older classes of compounds; the benzimidazoles, cholinergic agonists and macrocyclic lactones. We also consider newer anthelmintics, including emodepside, derquantel and tribendimidine. In the absence of vaccines for most parasite species, control of nematode parasites will continue to rely on anthelmintic drugs. As a consequence, vigilance in detecting drug resistance in parasite populations is required. Since resistance development appears almost inevitable, there is a continued and pressing need to fully understand the mode of action of these compounds. It is also necessary to identify new drug targets and drugs for the continued effective control of nematode parasites.

scholarly journals Genetic Profiling of thePlasmodium falciparumPopulation Using Antigenic Molecular Markers

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Purva Gupta ◽  
Ruchi Singh ◽  
Haris Khan ◽  
Adil Raza ◽  
Veena Yadavendu ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Molecular Mechanisms ◽  
Surface Protein ◽  
Merozoite Surface Protein ◽  
Parasite Population ◽  
Genetic Profile ◽  
Resistance Development ◽  
Genetic Profiling ◽  
Molecular Genotyping ◽  
Parasite Populations

About 50% of malaria infections in India are attributed toPlasmodium falciparumbut relatively little is known about the genetic structure of the parasite populations. The molecular genotyping of the parasite populations by merozoite surface protein(msp1 and msp2)and glutamate-rich protein (glurp) genes identifies the existing parasite population in the regions which help in understanding the molecular mechanisms involved in the parasite’s drive for survival. This study reveals the genetic profile of the parasite population in selected regions across the country with varying degree of endemicity among them. We also report the prevalence ofPfcrtmutations in this parasite population to evaluate the pattern of drug resistance development in them.

scholarly journals Amphotericin B and Other Polyenes—Discovery, Clinical Use, Mode of Action and Drug Resistance

2020 ◽  
Vol 6 (4) ◽  
pp. 321
Author(s):  
Hans Carolus ◽  
Siebe Pierson ◽  
Katrien Lagrou ◽  
Patrick Van Dijck
Keyword(s):  
Drug Resistance ◽  
Amphotericin B ◽  
Mode Of Action ◽  
Fungal Infections ◽  
Resistance Mechanisms ◽  
Antifungal Drugs ◽  
Clinical Use ◽  
Candida Auris ◽  
Resistance Development ◽  
Resistant Species

Although polyenes were the first broad spectrum antifungal drugs on the market, after 70 years they are still the gold standard to treat a variety of fungal infections. Polyenes such as amphotericin B have a controversial image. They are the antifungal drug class with the broadest spectrum, resistance development is still relatively rare and fungicidal properties are extensive. Yet, they come with a significant host toxicity that limits their use. Relatively recently, the mode of action of polyenes has been revised, new mechanisms of drug resistance were discovered and emergent polyene resistant species such as Candida auris entered the picture. This review provides a short description of the history and clinical use of polyenes, and focusses on the ongoing debate concerning their mode of action, the diversity of resistance mechanisms discovered to date and the most recent trends in polyene resistance development.

Discovery of an Unexpected Similarity in Ligand Binding Between BRD4 and PPARγ

2019 ◽  
Author(s):  
Lina Humbeck ◽  
Jette Pretzel ◽  
Saskia Spitzer ◽  
Oliver Koch
Keyword(s):  
Cancer Therapy ◽  
Drug Targets ◽  
Synergistic Effects ◽  
Complex Structure ◽  
Peroxisome Proliferator ◽  
Resistance Development ◽  
Peroxisome Proliferator Activated Receptor ◽  
Starting Point ◽  
Fundamental Research ◽  
Important Drug

Knowledge about interrelationships between different proteins is crucial in fundamental research for the elucidation of protein networks and pathways. Furthermore, it is especially critical in chemical biology to identify further key regulators of a disease and to take advantage of polypharmacology effects. A comprehensive scaffold-based analysis uncovered an unexpected relationship between bromodomain-containing protein 4 (BRD4) and peroxisome-proliferator activated receptor gamma (PPARγ). They are both important drug targets for cancer therapy and many more important diseases. Both proteins share binding site similarities near a common hydrophobic subpocket which should allow the design of a polypharmacology-based ligand targeting both proteins. Such a dual-BRD4-PPARγ-modulator could show synergistic effects with a higher efficacy or delayed resistance development in, for example, cancer therapy. Thereon, a complex structure of sulfasalazine was obtained that involves two bromodomains and could be a potential starting point for the design of a bivalent BRD4 inhibitor.

Genetic and Epigenetic Modulation of Drug Resistance in Cancer: Challenges and Opportunities

2020 ◽  
Vol 20 (14) ◽  
pp. 1114-1131 ◽  
Author(s):  
Kanisha Shah ◽  
Rakesh M. Rawal
Keyword(s):  
Drug Resistance ◽  
Drug Targets ◽  
Complex Disease ◽  
Cancer Therapies ◽  
Altered Expression ◽  
Acquired Drug Resistance ◽  
Challenges And Opportunities ◽  
Chemotherapeutic Treatment ◽  
Epigenetic Modulation ◽  
Targeted Drug Therapies

Cancer is a complex disease that has the ability to develop resistance to traditional therapies. The current chemotherapeutic treatment has become increasingly sophisticated, yet it is not 100% effective against disseminated tumours. Anticancer drugs resistance is an intricate process that ascends from modifications in the drug targets suggesting the need for better targeted therapies in the therapeutic arsenal. Advances in the modern techniques such as DNA microarray, proteomics along with the development of newer targeted drug therapies might provide better strategies to overcome drug resistance. This drug resistance in tumours can be attributed to an individual’s genetic differences, especially in tumoral somatic cells but acquired drug resistance is due to different mechanisms, such as cell death inhibition (apoptosis suppression) altered expression of drug transporters, alteration in drug metabolism epigenetic and drug targets, enhancing DNA repair and gene amplification. This review also focusses on the epigenetic modifications and microRNAs, which induce drug resistance and contributes to the formation of tumour progenitor cells that are not destroyed by conventional cancer therapies. Lastly, this review highlights different means to prevent the formation of drug resistant tumours and provides future directions for better treatment of these resistant tumours.

Mycobacterial DNA Replication as a Target for Antituberculosis Drug Discovery

2017 ◽  
Vol 17 (19) ◽  
pp. 2129-2142 ◽  
Author(s):  
Renata Płocinska ◽  
Malgorzata Korycka-Machala ◽  
Przemyslaw Plocinski ◽  
Jaroslaw Dziadek
Keyword(s):  
Drug Resistance ◽  
Dna Replication ◽  
Drug Targets ◽  
Rapid Development ◽  
New Drugs ◽  
Drug Resistant ◽  
Antituberculosis Drug ◽  
Nucleotide Synthesis ◽  
Antituberculosis Therapy ◽  
Optimal Drug

Background: Mycobacterium tuberculosis (M. tuberculosis), the causative agent of tuberculosis, is a leading infectious disease organism, causing millions of deaths each year. This serious pathogen has been greatly spread worldwide and recent years have observed an increase in the number of multi-drug resistant and totally drug resistant M. tuberculosis strains (WHO report, 2014). The danger of tuberculosis becoming an incurable disease has emphasized the need for the discovery of a new generation of antimicrobial agents. The development of novel alternative medical strategies, new drugs and the search for optimal drug targets are top priority areas of tuberculosis research. Factors: Key characteristics of mycobacteria include: slow growth, the ability to transform into a metabolically silent - latent state, intrinsic drug resistance and the relatively rapid development of acquired drug resistance. These factors make finding an ideal antituberculosis drug enormously challenging, even if it is designed to treat drug sensitive tuberculosis strains. A vast majority of canonical antibiotics including antituberculosis agents target bacterial cell wall biosynthesis or DNA/RNA processing. Novel therapeutic approaches are being tested to target mycobacterial cell division, twocomponent regulatory factors, lipid synthesis and the transition between the latent and actively growing states. Discussion and Conclusion: This review discusses the choice of cellular targets for an antituberculosis therapy, describes putative drug targets evaluated in the recent literature and summarizes potential candidates under clinical and pre-clinical development. We focus on the key cellular process of DNA replication, as a prominent target for future antituberculosis therapy. We describe two main pathways: the biosynthesis of nucleic acids precursors – the nucleotides, and the synthesis of DNA molecules. We summarize data regarding replication associated proteins that are critical for nucleotide synthesis, initiation, unwinding and elongation of the DNA during the replication process. They are pivotal processes required for successful multiplication of the bacterial cells and hence they are extensively investigated for the development of antituberculosis drugs. Finally, we summarize the most potent inhibitors of DNA synthesis and provide an up to date report on their status in the clinical trials.

scholarly journals 4E Interacting Protein as a Potential Novel Drug Target for Nucleoside Analogues in Trypanosoma Brucei

2021 ◽  
Vol 9 (4) ◽  
pp. 826
Author(s):  
Dorien Mabille ◽  
Camila Cardoso Santos ◽  
Rik Hendrickx ◽  
Mathieu Claes ◽  
Peter Takac ◽  
...  
Keyword(s):  
Mode Of Action ◽  
Drug Target ◽  
Drug Targets ◽  
De Novo ◽  
Treatment Options ◽  
Adenosine Kinase ◽  
Nucleoside Analogues ◽  
Purine Salvage ◽  
Interacting Protein ◽  
Novel Drug

Human African trypanosomiasis is a neglected parasitic disease for which the current treatment options are quite limited. Trypanosomes are not able to synthesize purines de novo and thus solely depend on purine salvage from the host environment. This characteristic makes players of the purine salvage pathway putative drug targets. The activity of known nucleoside analogues such as tubercidin and cordycepin led to the development of a series of C7-substituted nucleoside analogues. Here, we use RNA interference (RNAi) libraries to gain insight into the mode-of-action of these novel nucleoside analogues. Whole-genome RNAi screening revealed the involvement of adenosine kinase and 4E interacting protein into the mode-of-action of certain antitrypanosomal nucleoside analogues. Using RNAi lines and gene-deficient parasites, 4E interacting protein was found to be essential for parasite growth and infectivity in the vertebrate host. The essential nature of this gene product and involvement in the activity of certain nucleoside analogues indicates that it represents a potential novel drug target.

scholarly journals Label-Free Comparative Proteomics of Differentially Expressed Mycobacterium tuberculosis Protein in Rifampicin-Related Drug-Resistant Strains

Pathogens ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 607
Author(s):  
Nadeem Ullah ◽  
Ling Hao ◽  
Jo-Lewis Banga Ndzouboukou ◽  
Shiyun Chen ◽  
Yaqi Wu ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Drug Targets ◽  
Control Strategies ◽  
Multidrug Resistant ◽  
Differentially Expressed ◽  
Effective Control ◽  
Drug Resistant ◽  
Differentially Expressed Proteins ◽  
Label Free ◽  
Candidate Target

Rifampicin (RIF) is one of the most important first-line anti-tuberculosis (TB) drugs, and more than 90% of RIF-resistant (RR) Mycobacterium tuberculosis clinical isolates belong to multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB. In order to identify specific candidate target proteins as diagnostic markers or drug targets, differential protein expression between drug-sensitive (DS) and drug-resistant (DR) strains remains to be investigated. In the present study, a label-free, quantitative proteomics technique was performed to compare the proteome of DS, RR, MDR, and XDR clinical strains. We found iniC, Rv2141c, folB, and Rv2561 were up-regulated in both RR and MDR strains, while fadE9, espB, espL, esxK, and Rv3175 were down-regulated in the three DR strains when compared to the DS strain. In addition, lprF, mce2R, mce2B, and Rv2627c were specifically expressed in the three DR strains, and 41 proteins were not detected in the DS strain. Functional category showed that these differentially expressed proteins were mainly involved in the cell wall and cell processes. When compared to the RR strain, Rv2272, smtB, lpqB, icd1, and folK were up-regulated, while esxK, PPE19, Rv1534, rpmI, ureA, tpx, mpt64, frr, Rv3678c, esxB, esxA, and espL were down-regulated in both MDR and XDR strains. Additionally, nrp, PPE3, mntH, Rv1188, Rv1473, nadB, PPE36, and sseA were specifically expressed in both MDR and XDR strains, whereas 292 proteins were not identified when compared to the RR strain. When compared between MDR and XDR strains, 52 proteins were up-regulated, while 45 proteins were down-regulated in the XDR strain. 316 proteins were especially expressed in the XDR strain, while 92 proteins were especially detected in the MDR strain. Protein interaction networks further revealed the mechanism of their involvement in virulence and drug resistance. Therefore, these differentially expressed proteins are of great significance for exploring effective control strategies of DR-TB.

Valproic Acid (VPA) in Combination with Knockdown of AKT3 and PI3KCA Genes Inhibits Proliferation, Induces Apoptosis and Autophagy in T98G and U87MG Glioblastoma Multiforme Cells

2021 ◽  
Vol 8 (2) ◽  
Author(s):  
Paul-Samojedny M ◽  
◽  
Liduk E ◽  
Borkowska P ◽  
Kowalczyk M ◽  
...  
Keyword(s):  
Valproic Acid ◽  
Drug Resistance ◽  
Glioblastoma Multiforme ◽  
Cell Viability ◽  
Transfection Efficiency ◽  
Effective Control ◽  
Multi Drug Resistance ◽  
U87mg Cell ◽  
Glycoprotein P ◽  
Human Gbm

Purpose: Glioblastoma Multiforme (GBM) is a heterogenous and highly vascularized brain tumor that avoid apoptosis due to P-glycoprotein (P-gp) mediated multi-drug resistance. Therefore, development of new therapeutic strategies that induce apoptosis, inhibit proliferation, and overcome multi-drug resistance is urgently warranted. We examined the efficacy of combination of Valproic Acid (VPA) and knockdown of AKT3 and PI3KCA genes in human glioblastoma T98G and U87MG cell lines. Material and Methods: T98G and U87MG cells were transfected with AKT3 or PI3KCA siRNAs. Transfection efficiency was assessed using Flow Cytometry (FC) and fluorescence microscopy. The influence of AKT3 and PI3KCA siRNAs in combination with VPA on T98G and U87MG cell viability, proliferation, apoptosis and autophagy was evaluated as well. Alterations in the mRNA expression of apoptosis-related genes (CASP3 and Bid) were analyzed using QRT-PCR. Results: The transfection of T98G and U87MG cells with AKT3 or PI3KCA siRNAs and exposition on VPA led to a significant reduction in cell viability, the accumulation of subG1-phase cells and a reduced fraction of cells in the S and G2/M phases, apoptosis or necrosis induction and induction of autophagy. Conclusions: The siRNA-induced AKT3 and PI3KCA mRNA knockdown in combination with VPA may offer a novel therapeutic strategy to more effective control the growth of human GBM cells. Thus, knockdown of these genes in combination with valproic acid inhibits proliferation, induces apoptosis and autophagy in T98G and U87MG cells, but further studies are necessary to confirm a positive phenomenon for the treatment of GBM.

A Review of Corynespora cassiicola and Its Increasing Relevance to Tomato in Florida

2018 ◽  
Vol 19 (4) ◽  
pp. 303-309 ◽  
Author(s):  
Keevan J. MacKenzie ◽  
Leilani G. Sumabat ◽  
Katia V. Xavier ◽  
Gary E. Vallad
Keyword(s):  
Fungal Pathogen ◽  
Effective Control ◽  
Corynespora Cassiicola ◽  
Varietal Resistance ◽  
Vegetable Crop ◽  
Fresh Market ◽  
Resistance Development ◽  
Pathogen Diversity ◽  
Target Spot ◽  
Insight Into

Corynespora cassiicola is a highly diverse fungal pathogen that can infect more than 500 species of plants, including many economically important crops such as cotton, soybean, tomato, and cucumber. In Florida, the number one vegetable crop by market value are fresh-market tomatoes, which generate nearly half a billion dollars annually. Florida’s subtropical to tropical climate is conducive to infection and development of the target spot pathogen on tomato caused by C. cassiicola. There is no varietal resistance available for target spot of tomato, and preventative fungicide treatments are the primary method for control. In the last decade, C. cassiicola has been more frequently reported by Florida tomato growers, appearing not only more aggressive but also increasingly insensitive to various fungicides. This review brings together the most recent C. cassiicola literature, providing a history and understanding of the immense pathogen diversity and its relevance to tomato. It also provides insight into fungicide resistance development and pathogen survivability, which are important factors in providing effective control recommendations and in understanding the epidemiology of this disease, respectively.

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