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Current Opinion in Microbiology Aug 2023Antimicrobial susceptibility testing is the cornerstone of antibiotic treatments. Yet, active drugs are frequently unsuccessful in vivo and most clinical trials... (Review)
Review
Antimicrobial susceptibility testing is the cornerstone of antibiotic treatments. Yet, active drugs are frequently unsuccessful in vivo and most clinical trials investigating antibiotics fail. So far, bacterial survival strategies, other than drug resistance, have been largely ignored. As such, drug tolerance and persisters, allowing bacterial populations to survive during antibiotic treatments, could fill a gap in antibiotic susceptibility testing. Therefore, it remains critical to establish robust and scalable bacterial viability measures and to define the clinical relevance of bacterial survivors across various bacterial infections. If successful, these tools could improve drug design and development to prevent tolerance formation or target bacterial survivors, to ultimately reduce treatment failures and curb resistance evolution.
Topics: Humans; Anti-Bacterial Agents; Bacteria; Bacterial Infections; Drug Resistance, Bacterial; Drug Tolerance
PubMed: 37245488
DOI: 10.1016/j.mib.2023.102328 -
Nature Communications Apr 2022The ability of Mycobacterium tuberculosis (Mtb) to resist and tolerate antibiotics complicates the development of improved tuberculosis (TB) chemotherapies. Here we...
The ability of Mycobacterium tuberculosis (Mtb) to resist and tolerate antibiotics complicates the development of improved tuberculosis (TB) chemotherapies. Here we define the Mtb protein CinA as a major determinant of drug tolerance and as a potential target to shorten TB chemotherapy. By reducing the fraction of drug-tolerant persisters, genetic inactivation of cinA accelerated killing of Mtb by four antibiotics in clinical use: isoniazid, ethionamide, delamanid and pretomanid. Mtb ΔcinA was killed rapidly in conditions known to impede the efficacy of isoniazid, such as during nutrient starvation, during persistence in a caseum mimetic, in activated macrophages and during chronic mouse infection. Deletion of CinA also increased in vivo killing of Mtb by BPaL, a combination of pretomanid, bedaquiline and linezolid that is used to treat highly drug-resistant TB. Genetic and drug metabolism studies suggest that CinA mediates drug tolerance via cleavage of NAD-drug adducts.
Topics: Animals; Antitubercular Agents; Drug Tolerance; Isoniazid; Mice; Mycobacterium tuberculosis; Tuberculosis, Multidrug-Resistant
PubMed: 35459278
DOI: 10.1038/s41467-022-29832-1 -
Biological Psychiatry Jan 2020The relatively high efficacy of opioids, which have associated risks of addiction, tolerance, and dependence, for the management of acute and terminal pain has been a... (Review)
Review
The relatively high efficacy of opioids, which have associated risks of addiction, tolerance, and dependence, for the management of acute and terminal pain has been a major driver of the opioid crisis, together with the availability, overprescription, and diversion of these drugs. Eliminating opioids without an effective replacement is, however, no solution, as it substitutes one major problem with another. To deal successfully with the opioid crisis, we need to discover novel analgesics whose mechanisms do not involve the mu opioid receptor but that have high analgesic potency and low risk of adverse effects, particularly no abuse liability. The question is how to achieve this. There are several necessary elements; first, we need to understand the nature of pain and the mechanisms responsible for it, and second, we need to adopt novel and unbiased approaches to the identification and validation of pain targets.
Topics: Analgesics; Analgesics, Opioid; Chronic Pain; Drug Tolerance; Humans; Opioid-Related Disorders; Pain
PubMed: 31399256
DOI: 10.1016/j.biopsych.2019.06.017 -
PLoS Pathogens Oct 2020
Topics: Anti-Bacterial Agents; Drug Resistance, Bacterial; Drug Tolerance; Evolution, Molecular; Humans
PubMed: 33057409
DOI: 10.1371/journal.ppat.1008892 -
Pharmacology, Biochemistry, and Behavior Feb 2017This review examines the merits of 'food addiction' as an explanation of excessive eating (i.e., eating in excess of what is required to maintain a healthy body weight).... (Review)
Review
This review examines the merits of 'food addiction' as an explanation of excessive eating (i.e., eating in excess of what is required to maintain a healthy body weight). It describes various apparent similarities in appetites for foods and drugs. For example, conditioned environmental cues can arouse food and drug-seeking behaviour, 'craving' is an experience reported to precede eating and drug taking, 'bingeing' is associated with both eating and drug use, and conditioned and unconditioned tolerance occurs to food and drug ingestion. This is to be expected, as addictive drugs tap into the same processes and systems that evolved to motivate and control adaptive behaviours, including eating. The evidence, however, shows that drugs of abuse have more potent effects than foods, particularly in respect of their neuroadaptive effects that make them 'wanted.' While binge eating has been conceptualised as form of addictive behaviour, it is not a major cause of excessive eating, because binge eating has a far lower prevalence than obesity. Rather, it is proposed that obesity results from recurrent overconsumption of energy dense foods. Such foods are, relatedly, both attractive and (calorie for calorie) weakly satiating. Limiting their availability could partially decrease excessive eating and consequently decrease obesity. Arguably, persuading policy makers that these foods are addictive could support such action. However, blaming excessive eating on food addiction could be counterproductive, because it risks trivialising serious addictions, and because the attribution of excessive eating to food addiction implies an inability to control one's eating. Therefore, attributing everyday excessive eating to food addiction may neither explain nor significantly help reduce this problem.
Topics: Appetite; Bulimia; Craving; Drug Tolerance; Drug-Seeking Behavior; Humans; Motivation; Obesity; Reward; Substance Withdrawal Syndrome; Substance-Related Disorders
PubMed: 28063947
DOI: 10.1016/j.pbb.2017.01.001 -
Current Topics in Behavioral... 2018Discriminative stimulus and other drug effects are determined by the concentration of drug at its target receptor and by the pharmacodynamic consequences of... (Review)
Review
Discriminative stimulus and other drug effects are determined by the concentration of drug at its target receptor and by the pharmacodynamic consequences of drug-receptor interaction. For in vivo procedures such as drug discrimination, drug concentration at receptors in a given anatomical location (e.g., the brain) is determined both by the dose of drug administered and by pharmacokinetic processes of absorption, distribution, metabolism, and excretion that deliver drug to and from that anatomical location. Drug discrimination data are often analyzed by strategies of dose-effect analysis to determine parameters such as potency and efficacy. Pharmacokinetic-Pharmacodynamic (PKPD) analysis is an alternative to conventional dose-effect analysis, and it relates drug effects to a measure of drug concentration in a body compartment (e.g., venous blood) rather than to drug dose. PKPD analysis can yield insights on pharmacokinetic and pharmacodynamic determinants of drug action. PKPD analysis can also facilitate translational research by identifying species differences in pharmacokinetics and providing a basis for integrating these differences into interpretation of drug effects. Examples are discussed here to illustrate the application of PKPD analysis to the evaluation of drug effects in rhesus monkeys trained to discriminate cocaine from saline.
Topics: Animals; Discrimination, Psychological; Drug Tolerance; Humans; Prodrugs; Psychotropic Drugs
PubMed: 27571746
DOI: 10.1007/7854_2016_36 -
Cell Mar 2018Antibiotic tolerance, the capacity of genetically susceptible bacteria to survive the lethal effects of antibiotic treatment, plays a critical and underappreciated role... (Review)
Review
Antibiotic tolerance, the capacity of genetically susceptible bacteria to survive the lethal effects of antibiotic treatment, plays a critical and underappreciated role in the disease burden of bacterial infections. Here, we take a pathogen-by-pathogen approach to illustrate the clinical significance of antibiotic tolerance and discuss how the physiology of specific pathogens in their infection environments impacts the mechanistic underpinnings of tolerance. We describe how these insights are leading to the development of species-specific therapeutic strategies for targeting antibiotic tolerance and highlight experimental platforms that are enabling us to better understand the complexities of drug-tolerant pathogens in in vivo settings.
Topics: Animals; Anti-Bacterial Agents; Bacteria; Bacterial Infections; Bacterial Physiological Phenomena; Biofilms; Drug Tolerance; Host-Pathogen Interactions; Humans; Species Specificity
PubMed: 29522744
DOI: 10.1016/j.cell.2018.01.037 -
Ptchd1 mediates opioid tolerance via cholesterol-dependent effects on μ-opioid receptor trafficking.Nature Neuroscience Sep 2022Repeated exposure to opioids causes tolerance, which limits their analgesic utility and contributes to overdose and abuse liability. However, the molecular mechanisms...
Repeated exposure to opioids causes tolerance, which limits their analgesic utility and contributes to overdose and abuse liability. However, the molecular mechanisms underpinning tolerance are not well understood. Here, we used a forward genetic screen in Caenorhabditis elegans for unbiased identification of genes regulating opioid tolerance which revealed a role for PTR-25/Ptchd1. We found that PTR-25/Ptchd1 controls μ-opioid receptor trafficking and that these effects were mediated by the ability of PTR-25/Ptchd1 to control membrane cholesterol content. Electrophysiological studies showed that loss of Ptchd1 in mice reduced opioid-induced desensitization of neurons in several brain regions and the peripheral nervous system. Mice and C. elegans lacking Ptchd1/PTR-25 display similarly augmented responses to opioids. Ptchd1 knockout mice fail to develop analgesic tolerance and have greatly diminished somatic withdrawal. Thus, we propose that Ptchd1 plays an evolutionarily conserved role in protecting the μ-opioid receptor against overstimulation.
Topics: Analgesics, Opioid; Animals; Caenorhabditis elegans; Cholesterol; Drug Tolerance; Membrane Proteins; Mice; Mice, Knockout; Morphine; Receptors, Opioid, mu
PubMed: 35982154
DOI: 10.1038/s41593-022-01135-0 -
Current Opinion in Pharmacology Dec 2017The prevailing opioid crisis has necessitated the need to understand mechanisms leading to addiction and tolerance, the major contributors to overdose and death and to... (Review)
Review
The prevailing opioid crisis has necessitated the need to understand mechanisms leading to addiction and tolerance, the major contributors to overdose and death and to develop strategies for developing drugs for pain treatment that lack abuse liability and side-effects. Opioids are commonly used for treatment of pain and symptoms of inflammatory bowel disease. The significant effect of opioids in the gut, both acute and chronic, includes persistent constipation and paradoxically may also worsen pain symptoms. Recent work has suggested a significant role of the gastrointestinal microbiome in behavioral responses to opioids, including the development of tolerance to its pain-relieving effects. In this review, we present current concepts of gut-brain interaction in analgesic tolerance to opioids and suggest that peripheral mechanisms emanating from the gut can profoundly affect central control of opioid function.
Topics: Analgesics, Opioid; Animals; Brain; Drug Tolerance; Humans; Intestines
PubMed: 29145012
DOI: 10.1016/j.coph.2017.10.012 -
Pain Research & Management 2019Morphine has unfavorable side effects including analgesic tolerance. Morphine tolerance counteracts analgesic efficacy and drives dose escalation. The mechanisms... (Review)
Review
Morphine has unfavorable side effects including analgesic tolerance. Morphine tolerance counteracts analgesic efficacy and drives dose escalation. The mechanisms underlying morphine tolerance remain disputed, which has prevented the development of therapies to maximize and sustain analgesic efficacy. Morphine tolerance is an adaptive process induced by chronic morphine that has been shown to result from complex alterations at the molecular level with opioid receptors (MORs), as well as at the synaptic, cellular, and circuit levels. MicroRNAs are noncoding RNAs that have been proposed to regulate gene expression and degradation at the posttranscriptional level, including the MOR, as well as synaptic plasticity and neuroplasticity, in both the peripheral and central nervous systems. This review covers some of the most striking microRNA functions involved in morphine tolerance and presents limitations on our knowledge of their physiological roles.
Topics: Analgesics, Opioid; Animals; Drug Tolerance; Humans; MicroRNAs; Morphine
PubMed: 31182985
DOI: 10.1155/2019/9432965