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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 -
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 -
Clinical Microbiology Reviews Dec 2020Successful treatment of tuberculosis (TB) can be hampered by populations that are temporarily able to survive antibiotic pressure in the absence of drug... (Review)
Review
Successful treatment of tuberculosis (TB) can be hampered by populations that are temporarily able to survive antibiotic pressure in the absence of drug resistance-conferring mutations, a phenomenon termed drug tolerance. We summarize findings on tolerance published in the past 20 years. Key responses to drug pressure are reduced growth rates, metabolic shifting, and the promotion of efflux pump activity. Metabolic shifts upon drug pressure mainly occur in 's lipid metabolism and redox homeostasis, with reduced tricarboxylic acid cycle activity in favor of lipid anabolism. Increased lipid anabolism plays a role in cell wall thickening, which reduces sensitivity to most TB drugs. In addition to these general mechanisms, drug-specific mechanisms have been described. Upon isoniazid exposure, reprograms several pathways associated with mycolic acid biosynthesis. Upon rifampicin exposure, upregulates the expression of its drug target Upon bedaquiline exposure, ATP synthesis is stimulated, and the transcription factors Rv0324 and Rv0880 are activated. A better understanding of 's responses to drug pressure will be important for the development of novel agents that prevent the development of drug tolerance following treatment initiation. Such agents could then contribute to novel TB treatment-shortening strategies.
Topics: Antitubercular Agents; Bacterial Proteins; Citric Acid Cycle; Drug Resistance, Multiple, Bacterial; Gene Expression Regulation, Bacterial; Humans; Lipid Metabolism; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Tuberculosis
PubMed: 33055230
DOI: 10.1128/CMR.00141-20 -
Nature Cancer Aug 2023Cell plasticity represents the ability of cells to be reprogrammed and to change their fate and identity, enabling homeostasis restoration and tissue regeneration... (Review)
Review
Cell plasticity represents the ability of cells to be reprogrammed and to change their fate and identity, enabling homeostasis restoration and tissue regeneration following damage. Cell plasticity also contributes to pathological conditions, such as cancer, enabling cells to acquire new phenotypic and functional features by transiting across distinct cell states that contribute to tumor initiation, progression, metastasis and resistance to therapy. Here, we review the intrinsic and extrinsic mechanisms driving cell plasticity that promote tumor growth and proliferation as well as metastasis and drug tolerance. Finally, we discuss how cell plasticity could be exploited for anti-cancer therapy.
Topics: Humans; Cell Plasticity; Neoplasms; Cell Transformation, Neoplastic; Homeostasis
PubMed: 37537300
DOI: 10.1038/s43018-023-00595-y -
The Journal of Clinical Psychiatry Sep 2021reatment-resistant schizophrenia (TRS) represents a major clinical challenge. The broad definition of TRS requires nonresponse to at least 2 sequential antipsychotic... (Review)
Review
reatment-resistant schizophrenia (TRS) represents a major clinical challenge. The broad definition of TRS requires nonresponse to at least 2 sequential antipsychotic trials of sufficient dose, duration, and adherence. Several demographic, clinical, and neurologic predictors are associated with TRS. Primary (or early) TRS is present from the beginning of therapy, while patients with secondary (or later-onset) TRS initially respond to antipsychotics but become resistant over time, often after relapses. Guidelines worldwide recognize clozapine as the most effective treatment option for TRS, but clozapine is underused due to various barriers. Importantly, studies indicate that response rates are higher when clozapine is initiated earlier in the treatment course. Side effects are common with clozapine, particularly in the first few weeks, but can mostly be managed without discontinuation; they do require proactive assessment, intervention, and reassurance for patients. Furthermore, plasma leucocyte and granulocyte levels must be monitored weekly during the first 18-26 weeks of treatment, and regularly thereafter, according to country regulations. Therapeutic drug monitoring of clozapine trough plasma levels is helpful to guide dosing, with greatest efficacy at plasma clozapine levels ≥350 µg/L, although this level is not universal. Notably, plasma clozapine levels are generally greater at lower doses in nonsmokers, patients with heavy caffeine consumption, in women, in obese people, in those with inflammation (including COVID-19 infection), and in older individuals. Earlier and broader use of clozapine in patients with TRS is an important measure to improve outcomes of patients with this most severe form of the illness.
Topics: Antipsychotic Agents; Clozapine; Drug Resistance; Drug Tolerance; Female; Humans; Male; Schizophrenia
PubMed: 34496461
DOI: 10.4088/JCP.MY20096AH1C -
The Journal of Clinical Investigation Oct 2022Although first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy is effective for treating EGFR-mutant non-small cell lung cancer...
Although first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy is effective for treating EGFR-mutant non-small cell lung cancer (NSCLC), it is now understood that drug-tolerant persister (DTP) cells escaping from initial treatment eventually drives drug resistance. Here, through integration of metabolomics and transcriptomics, we found that the neurotransmitter acetylcholine (ACh) was specifically accumulated in DTP cells, and demonstrated that treatment with EGFR-TKI heightened the expression of the rate-limiting enzyme choline acetyltransferase (ChAT) in ACh biosynthesis via YAP mediation. Genetic and pharmacological manipulation of ACh biosynthesis or ACh signaling could predictably regulate the extent of DTP formation in vitro and in vivo. Strikingly, pharmacologically targeting ACh/M3R signaling with an FDA-approved drug, darifenacin, retarded tumor relapse in vivo. Mechanistically, upregulated ACh metabolism mediated drug tolerance in part through activating WNT signaling via ACh muscarinic receptor 3 (M3R). Importantly, we showed that aberrant ACh metabolism in patients with NSCLC played a potential role in predicting EGFR-TKI response rate and progression-free survival. Our study therefore defines a therapeutic strategy - targeting the ACh/M3R/WNT axis - for manipulating EGFR TKI drug tolerance in the treatment of NSCLC.
Topics: Acetylcholine; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Choline O-Acetyltransferase; Drug Resistance, Neoplasm; Drug Tolerance; ErbB Receptors; Humans; Lung Neoplasms; Mutation; Neoplasm Recurrence, Local; Protein Kinase Inhibitors
PubMed: 36048538
DOI: 10.1172/JCI160152 -
Pharmacology, Biochemistry, and Behavior May 2021Alcohol tolerance refers to a lower effect of alcohol with repeated exposure. Although alcohol tolerance has been historically included in diagnostic manuals as one of... (Review)
Review
Alcohol tolerance refers to a lower effect of alcohol with repeated exposure. Although alcohol tolerance has been historically included in diagnostic manuals as one of the key criteria for a diagnosis of alcohol use disorder (AUD), understanding its neurobiological mechanisms has been neglected in preclinical studies. In this mini-review, we provide a theoretical framework for alcohol tolerance. We then briefly describe chronic tolerance, followed by a longer discussion of behavioral and neurobiological aspects that underlie rapid tolerance in rodent models. Glutamate/nitric oxide, γ-aminobutyric acid, opioids, serotonin, dopamine, adenosine, cannabinoids, norepinephrine, vasopressin, neuropeptide Y, neurosteroids, and protein kinase C all modulate rapid tolerance. Most studies have evaluated the ability of pharmacological manipulations to block the development of rapid tolerance, but only a few studies have assessed their ability to reverse already established tolerance. Notably, only a few studies analyzed sex differences. Neglected areas of study include the incorporation of a key element of tolerance that involves opponent process-like neuroadaptations. Compared with alcohol drinking models, models of rapid tolerance are relatively shorter in duration and are temporally defined, which make them suitable for combining with a wide range of classic and modern research tools, such as pharmacology, optogenetics, calcium imaging, in vivo electrophysiology, and DREADDs, for in-depth studies of tolerance. We conclude that studies of the neurobiology of alcohol tolerance should be revisited with modern conceptualizations of addiction and modern neurobiological tools. This may contribute to our understanding of AUD and uncover potential targets that can attenuate hazardous alcohol drinking.
Topics: Alcohol Drinking; Alcoholism; Animals; Behavior, Addictive; Brain; Disease Models, Animal; Dopamine; Drug Tolerance; Ethanol; Female; Glutamic Acid; Humans; Male; Mice; Neurobiology; Norepinephrine; Rats; Serotonin; Sex Characteristics
PubMed: 33631255
DOI: 10.1016/j.pbb.2021.173155 -
Cell Communication and Signaling : CCS May 2023Glioma is a common primary tumor of the central nervous system (CNS), with glioblastoma multiforme (GBM) being the most malignant, aggressive, and drug resistant. Most... (Review)
Review
Glioma is a common primary tumor of the central nervous system (CNS), with glioblastoma multiforme (GBM) being the most malignant, aggressive, and drug resistant. Most drugs are designed to induce cancer cell death, either directly or indirectly, but malignant tumor cells can always evade death and continue to proliferate, resulting in a poor prognosis for patients. This reflects our limited understanding of the complex regulatory network that cancer cells utilize to avoid death. In addition to classical apoptosis, pyroptosis, ferroptosis, and autophagy are recognized as key cell death modalities that play significant roles in tumor progression. Various inducers or inhibitors have been discovered to target the related molecules in these pathways, and some of them have already been translated into clinical treatment. In this review, we summarized recent advances in the molecular mechanisms of inducing or inhibiting pyroptosis, ferroptosis, or autophagy in GBM, which are important for treatment or drug tolerance. We also discussed their links with apoptosis to better understand the mutual regulatory network among different cell death processes. Video Abstract.
Topics: Humans; Glioblastoma; Temozolomide; Ferroptosis; Pyroptosis; Brain Neoplasms; Apoptosis; Autophagy; Cell Line, Tumor
PubMed: 37208730
DOI: 10.1186/s12964-023-01108-1 -
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