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.

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.

scholarly journals Resistance to histone deacetylase inhibitors confers hypersensitivity to oncolytic reovirus therapy

2020 ◽  
Vol 4 (20) ◽  
pp. 5297-5310
Author(s):  
Shariful Islam ◽  
Claudia M. Espitia ◽  
Daniel O. Persky ◽  
Jennifer S. Carew ◽  
Steffan T. Nawrocki
Keyword(s):  
Histone Deacetylase ◽  
Hdac Inhibitor ◽  
Histone Deacetylase Inhibitors ◽  
Molecular Mechanisms ◽  
Hdac Inhibitors ◽  
Cross Resistance ◽  
Drug Resistant ◽  
In Vivo Models ◽  
Clinical Issue ◽  
Resistant Cells

Abstract Despite the promising antilymphoma activity of histone deacetylase (HDAC) inhibitors as a drug class, resistance is a significant clinical issue. Elucidating the molecular mechanisms driving HDAC inhibitor resistance and/or the specific targets that are altered in drug-resistant cells may facilitate the development of strategies that overcome drug resistance and are more effective for refractory patients. We generated novel T-cell lymphoma (TCL) cell line models of acquired resistance to the HDAC inhibitor belinostat to identify potential effective therapies. Belinostat-resistant cells displayed significant cross-resistance to other HDAC inhibitors including romidepsin, panobinostat, and vorinostat. Consistent with a lack of sensitivity to HDAC inhibitors, the resistant cells failed to induce increased acetylated histones. Drug-resistant cells featured significantly decreased expression of the key antiviral mediators IRF1 and STAT1. On the basis of these findings, we investigated the efficacy of the clinical formulation of reovirus (Reolysin) in parental and drug-resistant models. Our investigation revealed that HDAC inhibitor–resistant cells displayed enhanced vulnerability to reovirus replication and cell death in both in vitro and in vivo models compared with their parental counterparts. Importantly, Reolysin also significantly increased the antilymphoma activity of belinostat in HDAC inhibitor–resistant cells. Our data demonstrate that Reolysin alone or in combination with belinostat is a novel therapeutic strategy to treat TCL patients who develop resistance to HDAC inhibitors.

scholarly journals Novel Regulatory Mechanisms of Pathogenicity and Virulence to Combat MDR inCandida albicans

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Saif Hameed ◽  
Zeeshan Fatima
Keyword(s):  
Drug Resistance ◽  
Molecular Mechanisms ◽  
Opportunistic Pathogen ◽  
Antifungal Drugs ◽  
Regulatory Mechanisms ◽  
Cross Resistance ◽  
Signaling Networks ◽  
Antifungal Drug Resistance ◽  
Human Fungal Pathogen ◽  
Major Factors

Continuous deployment of antifungals in treating infections caused by dimorphic opportunistic pathogenCandida albicanshas led to the emergence of drug resistance resulting in cross-resistance to many unrelated drugs, a phenomenon termed multidrug resistance (MDR). Despite the current understanding of major factors which contribute to MDR mechanisms, there are many lines of evidence suggesting that it is a complex interplay of multiple factors which may be contributed by still unknown mechanisms. Coincidentally with the increased usage of antifungal drugs, the number of reports for antifungal drug resistance has also increased which further highlights the need for understanding novel molecular mechanisms which can be explored to combat MDR, namely, ROS, iron, hypoxia, lipids, morphogenesis, and transcriptional and signaling networks. Considering the worrying evolution of MDR and significance ofC. albicansbeing the most prevalent human fungal pathogen, this review summarizes these new regulatory mechanisms which could be exploited to prevent MDR development inC. albicansas established from recent studies.

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.

scholarly journals Drug-Resistant Infection: Causes, Consequences, and Responses

2020 ◽  
pp. 3-18
Author(s):  
Euzebiusz Jamrozik ◽  
Michael J. Selgelid
Keyword(s):  
Public Health ◽  
Drug Resistance ◽  
Well Being ◽  
Microbial Evolution ◽  
Antimicrobial Use ◽  
Drug Resistant ◽  
Genetic Determinants ◽  
Policy Responses ◽  
Hygiene Practices ◽  
Resistant Infection

Abstract This chapter provides an overview of the causes and consequences of, and possible policy responses to, the problem of drug resistance. Throughout, we highlight the ways that ethical and conceptual analyses can help to clarify relevant issues and improve policy, especially in public health, broadly conceived. Drug resistant pathogens arise, persist, spread, and produce harm due to a complex set of causes: biological processes (e.g., related to microbial evolution, the transmission of genetic determinants of resistance between microbes, and human host immunity) as well as human behaviors (e.g., antimicrobial use and hygiene practices) and other social factors (e.g., access to clean water, sanitation, healthcare, and antimicrobials). Furthermore, the ethically salient consequences of drug resistance include not only morbidity and mortality from untreatable infections (that are often inequitably distributed), but also broader effects on human freedom, privacy, and well-being. Public health ethicists are ideally placed to identify and weigh the values that might be promoted or compromised by potential policies and/or interventions that aim to address the problem of drug resistance. This chapter concludes by discussing potential policy responses, including those related to surveillance, research, animal and human antimicrobial use, the broader social determinants of health, infection control practices, and vaccination.

scholarly journals Mitochondrial dysfunctions trigger the calcium signaling-dependent fungal multidrug resistance

2019 ◽  
Vol 117 (3) ◽  
pp. 1711-1721 ◽  
Author(s):  
Yeqi Li ◽  
Yuanwei Zhang ◽  
Chi Zhang ◽  
Hongchen Wang ◽  
Xiaolei Wei ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Multidrug Resistance ◽  
Mitochondrial Dysfunction ◽  
Calcium Signaling ◽  
Molecular Mechanisms ◽  
Expression Profiles ◽  
Drug Binding ◽  
Fitness Cost ◽  
Drug Resistant ◽  
Resistant Mutants

Drug resistance in fungal pathogens has risen steadily over the past decades due to long-term azole therapy or triazole usage in agriculture. Modification of the drug target protein to prevent drug binding is a major recognized route to induce drug resistance. However, mechanisms for nondrug target-induced resistance remain only loosely defined. Here, we explore the molecular mechanisms of multidrug resistance resulted from an efficient adaptation strategy for survival in drug environments in the human pathogen Aspergillus fumigatus. We show that mutants conferring multidrug resistance are linked with mitochondrial dysfunction induced by defects in heme A biosynthesis. Comparison of the gene expression profiles between the drug-resistant mutants and the parental wild-type strain shows that multidrug-resistant transporters, chitin synthases, and calcium-signaling-related genes are significantly up-regulated, while scavenging mitochondrial reactive oxygen species (ROS)-related genes are significantly down-regulated. The up-regulated-expression genes share consensus calcium-dependent serine threonine phosphatase-dependent response elements (the binding sites of calcium-signaling transcription factor CrzA). Accordingly, drug-resistant mutants show enhanced cytosolic Ca2+ transients and persistent nuclear localization of CrzA. In comparison, calcium chelators significantly restore drug susceptibility and increase azole efficacy either in laboratory-derived or in clinic-isolated A. fumigatus strains. Thus, the mitochondrial dysfunction as a fitness cost can trigger calcium signaling and, therefore, globally up-regulate a series of embedding calcineurin-dependent–response-element genes, leading to antifungal resistance. These findings illuminate how fitness cost affects drug resistance and suggest that disruption of calcium signaling might be a promising therapeutic strategy to fight against nondrug target-induced drug resistance.

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 Isoniazid, The Frontline of Resistance in Mycobacterium tuberculosis

2002 ◽  
Vol 6 (2) ◽  
Author(s):  
James B. Whitney ◽  
Mark A. Wainberg
Keyword(s):  
Public Health ◽  
Drug Resistance ◽  
Mycobacterium Tuberculosis ◽  
Genome Sequence ◽  
Molecular Mechanisms ◽  
Close Association ◽  
Drug Resistant ◽  
Efficient Control ◽  
Control And Management ◽  
Developed Nations

Tuberculosis is an ancient disease that has held close association with humans for millennia. Through persistence, this remarkably successful organism has managed to infect an estimated third of the world's population. Declining rates of tuberculosis in developed nations have masked an emerging epidemic of drug resistant cases that have been reported in almost every country under scrutiny. The recent completion of the genome sequence of Mycobacterium tuberculosis has mandated more efficient control and management of this disease. The momentum for this public health imperative will come from information gleaned from advances in genomics and related technologies towards deciphering molecular mechanisms of mycobacterial drug resistance.

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