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Nature Reviews. Microbiology Jun 2020Systemic fungal infections pose a serious clinical problem. Treatment options are limited, and antifungal drug resistance is increasing. In addition, a substantial... (Review)
Review
Systemic fungal infections pose a serious clinical problem. Treatment options are limited, and antifungal drug resistance is increasing. In addition, a substantial proportion of patients do not respond to therapy despite being infected with fungi that are susceptible to the drug. The discordance between overall treatment outcome and low levels of clinical resistance may be attributable to antifungal drug tolerance. In this Review, we define and distinguish resistance and tolerance and discuss the current understanding of the molecular, genetic and physiological mechanisms that contribute to those phenomena. Distinguishing tolerance from resistance might provide important insights into the reasons for treatment failure in some settings.
Topics: Antifungal Agents; Candida; Drug Resistance, Fungal; Drug Tolerance; Humans; Microbial Sensitivity Tests
PubMed: 32047294
DOI: 10.1038/s41579-019-0322-2 -
Nature Reviews. Microbiology Apr 2016Antibiotic tolerance is associated with the failure of antibiotic treatment and the relapse of many bacterial infections. However, unlike resistance, which is commonly... (Review)
Review
Antibiotic tolerance is associated with the failure of antibiotic treatment and the relapse of many bacterial infections. However, unlike resistance, which is commonly measured using the minimum inhibitory concentration (MIC) metric, tolerance is poorly characterized, owing to the lack of a similar quantitative indicator. This may lead to the misclassification of tolerant strains as resistant, or vice versa, and result in ineffective treatments. In this Opinion article, we describe recent studies of tolerance, resistance and persistence, outlining how a clear and distinct definition for each phenotype can be developed from these findings. We propose a framework for classifying the drug response of bacterial strains according to these definitions that is based on the measurement of the MIC together with a recently defined quantitative indicator of tolerance, the minimum duration for killing (MDK). Finally, we discuss genes that are associated with increased tolerance - the 'tolerome' - as targets for treating tolerant bacterial strains.
Topics: Anti-Bacterial Agents; Bacteria; Drug Resistance, Bacterial; Drug Tolerance; Microbial Sensitivity Tests
PubMed: 27080241
DOI: 10.1038/nrmicro.2016.34 -
Cell Host & Microbe Jul 2019Biofilms are surface-associated bacterial communities that play both beneficial and harmful roles in nature, medicine, and industry. Tolerant and persister cells are... (Review)
Review
Biofilms are surface-associated bacterial communities that play both beneficial and harmful roles in nature, medicine, and industry. Tolerant and persister cells are thought to underlie biofilm-related bacterial recurrence in medical and industrial contexts. Here, we review recent progress aimed at understanding the mechanical features that drive biofilm resilience and the biofilm formation process at single-cell resolution. We discuss findings regarding mechanisms underlying bacterial tolerance and persistence in biofilms and how these phenotypes are linked to antibiotic resistance. New strategies for combatting tolerance and persistence in biofilms and possible methods for biofilm eradication are highlighted to inspire future development.
Topics: Anti-Bacterial Agents; Bacteria; Biofilms; Drug Resistance, Bacterial; Drug Tolerance; Microbial Viability
PubMed: 31295420
DOI: 10.1016/j.chom.2019.06.002 -
Nature Reviews. Microbiology Jul 2019Increasing concerns about the rising rates of antibiotic therapy failure and advances in single-cell analyses have inspired a surge of research into antibiotic... (Review)
Review
Increasing concerns about the rising rates of antibiotic therapy failure and advances in single-cell analyses have inspired a surge of research into antibiotic persistence. Bacterial persister cells represent a subpopulation of cells that can survive intensive antibiotic treatment without being resistant. Several approaches have emerged to define and measure persistence, and it is now time to agree on the basic definition of persistence and its relation to the other mechanisms by which bacteria survive exposure to bactericidal antibiotic treatments, such as antibiotic resistance, heteroresistance or tolerance. In this Consensus Statement, we provide definitions of persistence phenomena, distinguish between triggered and spontaneous persistence and provide a guide to measuring persistence. Antibiotic persistence is not only an interesting example of non-genetic single-cell heterogeneity, it may also have a role in the failure of antibiotic treatments. Therefore, it is our hope that the guidelines outlined in this article will pave the way for better characterization of antibiotic persistence and for understanding its relevance to clinical outcomes.
Topics: Anti-Bacterial Agents; Bacteria; Biomedical Research; Drug Tolerance; Guidelines as Topic; Terminology as Topic
PubMed: 30980069
DOI: 10.1038/s41579-019-0196-3 -
Nature Communications Mar 2021Tyrosine kinase inhibitors were found to be clinically effective for treatment of patients with certain subsets of cancers carrying somatic mutations in receptor...
Tyrosine kinase inhibitors were found to be clinically effective for treatment of patients with certain subsets of cancers carrying somatic mutations in receptor tyrosine kinases. However, the duration of clinical response is often limited, and patients ultimately develop drug resistance. Here, we use single-cell RNA sequencing to demonstrate the existence of multiple cancer cell subpopulations within cell lines, xenograft tumors and patient tumors. These subpopulations exhibit epigenetic changes and differential therapeutic sensitivity. Recurrently overrepresented ontologies in genes that are differentially expressed between drug tolerant cell populations and drug sensitive cells include epithelial-to-mesenchymal transition, epithelium development, vesicle mediated transport, drug metabolism and cholesterol homeostasis. We show analysis of identified markers using the LINCS database to predict and functionally validate small molecules that target selected drug tolerant cell populations. In combination with EGFR inhibitors, crizotinib inhibits the emergence of a defined subset of EGFR inhibitor-tolerant clones. In this study, we describe the spectrum of changes associated with drug tolerance and inhibition of specific tolerant cell subpopulations with combination agents.
Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Cholesterol; Drug Combinations; Drug Discovery; Drug Resistance, Neoplasm; Drug Tolerance; Epithelial-Mesenchymal Transition; ErbB Receptors; Gene Expression Regulation, Neoplastic; Heterografts; Humans; Mutation; Neoplasms; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases; U937 Cells
PubMed: 33712615
DOI: 10.1038/s41467-021-21884-z -
Trends in Microbiology Apr 2019The Eagle effect describes a phenomenon in which bacteria or fungi exposed to concentrations of antibiotic higher than an optimal bactericidal concentration (OBC) have... (Review)
Review
The Eagle effect describes a phenomenon in which bacteria or fungi exposed to concentrations of antibiotic higher than an optimal bactericidal concentration (OBC) have paradoxically improved levels of survival than at the OBC due to a decreased net rate of cell death. Despite extensive observational reports of this effect in different microorganisms, its underlying mode of action is not well understood. Although aspects of the Eagle effect resemble persistence, there is strong evidence that these phenomena are substantially different phenotypic responses to antibiotic treatment. We present an overview of the microorganism and antimicrobial combinations in which the Eagle effect has been observed. Proposed underlying mechanism(s) are assessed, and the Eagle effect and microbial persistence are compared and contrasted. The clinical relevance of the Eagle effect is reviewed, incorporating evidence from experimental in vitro and in vivo studies, as well as clinical reports.
Topics: Animals; Anti-Infective Agents; Bacteria; Dose-Response Relationship, Drug; Drug Combinations; Drug Resistance, Bacterial; Drug Tolerance; Fungi; Gene Expression Regulation, Bacterial; Humans; Microbial Sensitivity Tests
PubMed: 30448198
DOI: 10.1016/j.tim.2018.10.007 -
Science Advances Feb 2023Opioid tolerance develops as a learned response to drug-associated cues and is thus a dynamic effect modulated by the interaction between drug and environment. (Review)
Review
Opioid tolerance develops as a learned response to drug-associated cues and is thus a dynamic effect modulated by the interaction between drug and environment.
Topics: Analgesics, Opioid; Conditioning, Classical; Drug Tolerance; Learning; Cues
PubMed: 36753539
DOI: 10.1126/sciadv.adg6086 -
Neuron Nov 2023Chronic pain is a tremendous burden for afflicted individuals and society. Although opioids effectively relieve pain, significant adverse outcomes limit their utility...
Chronic pain is a tremendous burden for afflicted individuals and society. Although opioids effectively relieve pain, significant adverse outcomes limit their utility and efficacy. To investigate alternate pain control mechanisms, we explored cholinergic signaling in the ventrolateral periaqueductal gray (vlPAG), a critical nexus for descending pain modulation. Biosensor assays revealed that pain states decreased acetylcholine release in vlPAG. Activation of cholinergic projections from the pedunculopontine tegmentum to vlPAG relieved pain, even in opioid-tolerant conditions, through ⍺7 nicotinic acetylcholine receptors (nAChRs). Activating ⍺7 nAChRs with agonists or stimulating endogenous acetylcholine inhibited vlPAG neuronal activity through Ca and peroxisome proliferator-activated receptor α (PPAR⍺)-dependent signaling. In vivo 2-photon imaging revealed that chronic pain induces aberrant excitability of vlPAG neuronal ensembles and that ⍺7 nAChR-mediated inhibition of these cells relieves pain, even after opioid tolerance. Finally, pain relief through these cholinergic mechanisms was not associated with tolerance, reward, or withdrawal symptoms, highlighting its potential clinical relevance.
Topics: Rats; Animals; Humans; Analgesics, Opioid; Chronic Pain; Acetylcholine; Rats, Sprague-Dawley; Pain Measurement; Drug Tolerance; Periaqueductal Gray; Cholinergic Agents; Receptors, Nicotinic
PubMed: 37734381
DOI: 10.1016/j.neuron.2023.08.017 -
Peptides Nov 2023This paper is the forty-fifth consecutive installment of the annual anthological review of research concerning the endogenous opioid system, summarizing articles... (Review)
Review
This paper is the forty-fifth consecutive installment of the annual anthological review of research concerning the endogenous opioid system, summarizing articles published during 2022 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides and receptors as well as effects of opioid/opiate agonists and antagonists. The review is subdivided into the following specific topics: molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors (1), the roles of these opioid peptides and receptors in pain and analgesia in animals (2) and humans (3), opioid-sensitive and opioid-insensitive effects of nonopioid analgesics (4), opioid peptide and receptor involvement in tolerance and dependence (5), stress and social status (6), learning and memory (7), eating and drinking (8), drug abuse and alcohol (9), sexual activity and hormones, pregnancy, development and endocrinology (10), mental illness and mood (11), seizures and neurologic disorders (12), electrical-related activity and neurophysiology (13), general activity and locomotion (14), gastrointestinal, renal and hepatic functions (15), cardiovascular responses (16), respiration and thermoregulation (17), and immunological responses (18).
Topics: Animals; Humans; Female; Pregnancy; Opioid Peptides; Analgesics, Opioid; Analgesia; Analgesics, Non-Narcotic; Drug Tolerance
PubMed: 37704079
DOI: 10.1016/j.peptides.2023.171095 -
Journal of Neuroscience Research Sep 2023As we all know, opioids are the drugs of choice for treating severe pain. However, very often, opioid use leads to tolerance, dependence, and hyperalgesia. Therefore,... (Review)
Review
As we all know, opioids are the drugs of choice for treating severe pain. However, very often, opioid use leads to tolerance, dependence, and hyperalgesia. Therefore, understanding the mechanisms underlying opioid tolerance and designing strategies for increasing the efficacy of opioids in chronic pain are important areas of research. Microglia are brain macrophages that remove debris and dead cells from the brain and participate in immune defense of the central nervous system during an insult or injury. However, recent studies indicate that microglial activation and generation of proinflammatory molecules (e.g., cytokines, nitric oxide, eicosanoids, etc.) in the brain may contribute to opioid tolerance and other side effects of opioid use. In this review, we will summarize the evidence and possible mechanisms by which proinflammatory molecules produced by activated microglia may antagonize the analgesic effect induced by opioids, and thus, lead to opioid tolerance. We will also delineate specific examples of studies that suggest therapeutic targets to counteract the development of tolerance clinically using suppressors of microglial inflammation.
Topics: Humans; Analgesics, Opioid; Microglia; Morphine; Drug Tolerance; Hyperalgesia; Inflammation
PubMed: 37186407
DOI: 10.1002/jnr.25199