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Frontiers in Cellular and Infection... 2022Treatment of ( infections is particularly arduous. One challenge to effectively treating tuberculosis is that drug efficacy often fails to match drug efficacy This is... (Review)
Review
Treatment of ( infections is particularly arduous. One challenge to effectively treating tuberculosis is that drug efficacy often fails to match drug efficacy This is due to multiple reasons, including inadequate drug concentrations reaching at the site of infection and physiological changes of in response to host derived stresses that render the bacteria more tolerant to antibiotics. To more effectively and efficiently treat tuberculosis, it is necessary to better understand the physiologic state of that promotes drug tolerance in the host. Towards this end, multiple studies have converged on bacterial central carbon metabolism as a critical contributor to drug tolerance. In this review, we present the evidence that changes in central carbon metabolism can promote drug tolerance, depending on the environment surrounding . We posit that these metabolic pathways could be potential drug targets to stymie the development of drug tolerance and enhance the efficacy of current antimicrobial therapy.
Topics: Carbon; Drug Tolerance; Humans; Metabolic Networks and Pathways; Mycobacterium tuberculosis; Tuberculosis, Lymph Node
PubMed: 36072222
DOI: 10.3389/fcimb.2022.958555 -
Frontiers in Cellular and Infection... 2022Combination therapy is necessary to treat tuberculosis to decrease the rate of disease relapse and prevent the acquisition of drug resistance, and shorter regimens are... (Review)
Review
Combination therapy is necessary to treat tuberculosis to decrease the rate of disease relapse and prevent the acquisition of drug resistance, and shorter regimens are urgently needed. The adaptation of to various lesion microenvironments in infection induces various states of slow replication and non-replication and subsequent antibiotic tolerance. This non-heritable tolerance to treatment necessitates lengthy combination therapy. Therefore, it is critical to develop combination therapies that specifically target the different types of drug-tolerant cells in infection. As new tools to study drug combinations earlier in the drug development pipeline are being actively developed, we must consider how to best model the drug-tolerant cells to use these tools to design the best antibiotic combinations that target those cells and shorten tuberculosis therapy. In this review, we discuss the factors underlying types of drug tolerance, how combination therapy targets these populations of bacteria, and how drug tolerance is currently modeled for the development of tuberculosis multidrug therapy. We highlight areas for future studies to develop new tools that better model drug tolerance in tuberculosis infection specifically for combination therapy testing to bring the best drug regimens forward to the clinic.
Topics: Humans; Mycobacterium tuberculosis; Antitubercular Agents; Drug Therapy, Combination; Leprostatic Agents; Tuberculosis; Drug Tolerance
PubMed: 36733851
DOI: 10.3389/fcimb.2022.1085946 -
Experimental and Clinical... Aug 2020Increasing sensitivity due to alcohol intake has been explored using molecular and cellular mechanisms of sensitization and adaptive biobehavioral changes as well as... (Review)
Review
Increasing sensitivity due to alcohol intake has been explored using molecular and cellular mechanisms of sensitization and adaptive biobehavioral changes as well as through negative experiences of altered function during withdrawal. However, within both a preclinical and human laboratory setting, little has been elucidated toward understanding the neural substrates of decreased sensitivity to alcohol effects, that is, alcohol tolerance. More paradigms assessing alcohol tolerance are needed. Tolerance can be assessed through both self-reported response (subjective) and observed (objective) measurements. Therefore, sensitivity to alcohol is an exploitable variable that can be utilized to disentangle the diverse alcohol use disorder (AUD) phenotypical profile. This literature review focuses on preclinical models and human laboratory studies to evaluate alcohol tolerance and its modulating factors. Increased understanding of alcohol tolerance has the potential to reduce gaps between preclinical models and human laboratory studies to better evaluate the development of alcohol-related biobehavioral responses. Furthermore, alcohol tolerance can be used as an AUD phenotypic variable in randomized clinical trials designed for developing AUD therapies. (PsycInfo Database Record (c) 2020 APA, all rights reserved).
Topics: Alcohol Drinking; Alcoholism; Drug Tolerance; Ethanol; Humans; Research Design
PubMed: 32212746
DOI: 10.1037/pha0000366 -
The Journal of Biological Chemistry Jun 2016Microbial biofilms demonstrate a decreased susceptibility to antimicrobial agents. Various mechanisms have been proposed to be involved in this recalcitrance. We focus... (Review)
Review
Microbial biofilms demonstrate a decreased susceptibility to antimicrobial agents. Various mechanisms have been proposed to be involved in this recalcitrance. We focus on two of these factors. Firstly, the ability of sessile cells to actively mediate efflux of antimicrobial compounds has a profound impact on resistance and tolerance, and several studies point to the existence of biofilm-specific efflux systems. Secondly, biofilm-specific stress responses have a marked influence on cellular physiology, and contribute to the occurrence of persister cells. We provide an overview of the data that demonstrate that both processes are important for survival following exposure to antimicrobial agents.
Topics: Adaptation, Physiological; Anti-Infective Agents; Biofilms; Biological Transport; Drug Resistance, Bacterial; Drug Tolerance; Humans; Microbial Sensitivity Tests; Microbial Viability; Models, Biological
PubMed: 27129224
DOI: 10.1074/jbc.R115.707257 -
Anesthesiology Feb 2016
Review
Topics: Analgesics, Opioid; Drug Tolerance; Humans; Hyperalgesia
PubMed: 26594912
DOI: 10.1097/ALN.0000000000000963 -
Molecular Oncology Apr 2023Targeted therapies have become a mainstay in the treatment of cancer, but their long-term efficacy is compromised by acquired drug resistance. Acquired therapy... (Review)
Review
Targeted therapies have become a mainstay in the treatment of cancer, but their long-term efficacy is compromised by acquired drug resistance. Acquired therapy resistance develops via two phases-first through adaptive development of nongenetic drug tolerance, which is followed by stable resistance through the acquisition of genetic mutations. Drug tolerance has been described in practically all clinical cancer treatment contexts, and detectable drug-tolerant tumors are highly associated with treatment relapse and poor survival. Thereby, novel therapeutic strategies are needed to overcome cancer therapy tolerance. Recent studies have identified a critical role of mitochondrial mechanisms in defining cancer cell sensitivity to targeted therapies and the surprising effects of established cancer therapies on mitochondria. Here, these recent studies are reviewed emphasizing an emerging concept of triplet therapies including three compounds targeting different cancer cell vulnerabilities but including at least one compound that targets the mitochondria. These mitochondria-targeting triplet therapies have very promising preclinical effects in overcoming cancer therapy tolerance. Potential strategies of how to overcome challenges in the clinical translation of mitochondria-targeting triplet therapies are also discussed.
Topics: Humans; Drug Tolerance; Mitochondria; Neoplasms
PubMed: 36852624
DOI: 10.1002/1878-0261.13406 -
PLoS Pathogens Nov 2022Genetically susceptible bacteria can escape the action of bactericidal antibiotics through antibiotic tolerance or persistence. However, one major difference between the...
Genetically susceptible bacteria can escape the action of bactericidal antibiotics through antibiotic tolerance or persistence. However, one major difference between the two phenomena is their distinct penetrance within an isogenic population. While with antibiotic persistence, susceptible and persister cells co-exist, antibiotic tolerance affects the entire bacterial population. Here, we show that antibiotic tolerance can be achieved in numerous non-specific ways in vitro and during infection. More importantly, we highlight that, due to their impact on the entire bacterial population, these tolerance-inducing conditions completely mask persistence and the action of its molecular determinants. Finally, we show that even though tolerant populations display a high survival rate under bactericidal drug treatment, this feature comes at the cost of having impaired proliferation during infection. In contrast, persistence is a risk-limiting strategy that allows bacteria to survive antibiotic treatment without reducing the ability of the population to colonize their host. Altogether, our data emphasise that the distinction between these phenomena is of utmost importance to improve the design of more efficient antibiotic therapies.
Topics: Anti-Bacterial Agents; Bacteria; Drug Tolerance
PubMed: 36374854
DOI: 10.1371/journal.ppat.1010963 -
Alcohol Research & Health : the Journal... 2008Tolerance is defined as the diminished response to alcohol or other drugs over the course of repeated or prolonged exposure. This mechanism allows physiological... (Review)
Review
Tolerance is defined as the diminished response to alcohol or other drugs over the course of repeated or prolonged exposure. This mechanism allows physiological processes to achieve stability in a constantly changing environment. The onset of tolerance may occur within minutes, during a single exposure to alcohol (i.e., acute tolerance), or over longer timeframes and with prolonged exposure to alcohol (i.e., rapid or chronic tolerance). Changes in tolerance induced by alcohol may affect several processes at the molecular, cellular, or behavioral level. These effects often are interrelated and may be difficult to separate. This article describes changes at the molecular level that are related to the onset of acute, rapid, or chronic tolerance. It focuses on neuronal membrane-bound channels and the factors that affect their function and production, such as modification of protein synthesis and activity, interaction with the membrane lipid microenvironment, epigenetic effects on cytoplasmic regulation, and gene transcription. Also considered is the genetics of tolerance.
Topics: Alcohol Drinking; Animals; Drug Tolerance; Epigenesis, Genetic; Ethanol; Humans; Membrane Lipids; Membrane Proteins
PubMed: 23584007
DOI: No ID Found -
The Journal of Clinical Investigation Jul 2018Adverse drug reactions (ADRs) are a major obstacle to drug development, and some of these, including hypersensitivity reactions to the HIV reverse transcriptase...
Adverse drug reactions (ADRs) are a major obstacle to drug development, and some of these, including hypersensitivity reactions to the HIV reverse transcriptase inhibitor abacavir (ABC), are associated with HLA alleles, particularly HLA-B*57:01. However, not all HLA-B*57:01+ patients develop ADRs, suggesting that in addition to the HLA genetic risk, other factors may influence the outcome of the response to the drug. To study HLA-linked ADRs in vivo, we generated HLA-B*57:01-Tg mice and show that, although ABC activated Tg mouse CD8+ T cells in vitro in a HLA-B*57:01-dependent manner, the drug was tolerated in vivo. In immunocompetent Tg animals, ABC induced CD8+ T cells with an anergy-like phenotype that did not lead to ADRs. In contrast, in vivo depletion of CD4+ T cells prior to ABC administration enhanced DC maturation to induce systemic ABC-reactive CD8+ T cells with an effector-like and skin-homing phenotype along with CD8+ infiltration and inflammation in drug-sensitized skin. B7 costimulatory molecule blockade prevented CD8+ T cell activation. These Tg mice provide a model for ABC tolerance and for the generation of HLA-B*57:01-restricted, ABC-reactive CD8+ T cells dependent on both HLA genetic risk and immunoregulatory host factors.
Topics: Animals; Anti-HIV Agents; CD8-Positive T-Lymphocytes; Dideoxynucleosides; Disease Models, Animal; Drug Hypersensitivity; Drug Tolerance; Drug-Related Side Effects and Adverse Reactions; Female; HLA-B Antigens; Humans; In Vitro Techniques; Lymphocyte Activation; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Reverse Transcriptase Inhibitors
PubMed: 29782330
DOI: 10.1172/JCI99321 -
Nature Communications Mar 2023Candida glabrata is a major fungal pathogen notable for causing recalcitrant infections, rapid emergence of drug-resistant strains, and its ability to survive and...
Candida glabrata is a major fungal pathogen notable for causing recalcitrant infections, rapid emergence of drug-resistant strains, and its ability to survive and proliferate within macrophages. Resembling bacterial persisters, a subset of genetically drug-susceptible C. glabrata cells can survive lethal exposure to the fungicidal echinocandin drugs. Herein, we show that macrophage internalization induces cidal drug tolerance in C. glabrata, expanding the persister reservoir from which echinocandin-resistant mutants emerge. We show that this drug tolerance is associated with non-proliferation and is triggered by macrophage-induced oxidative stress, and that deletion of genes involved in reactive oxygen species detoxification significantly increases the emergence of echinocandin-resistant mutants. Finally, we show that the fungicidal drug amphotericin B can kill intracellular C. glabrata echinocandin persisters, reducing emergence of resistance. Our study supports the hypothesis that intra-macrophage C. glabrata is a reservoir of recalcitrant/drug-resistant infections, and that drug alternating strategies can be developed to eliminate this reservoir.
Topics: Drug Tolerance; Antifungal Agents; Echinocandins; Candida glabrata; Macrophages; Drug Resistance
PubMed: 36864040
DOI: 10.1038/s41467-023-36882-6