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EMBO Reports Dec 2020Antimicrobial resistance (AMR) and persistence are associated with an elevated risk of treatment failure and relapsing infections. They are thus important drivers of... (Review)
Review
Antimicrobial resistance (AMR) and persistence are associated with an elevated risk of treatment failure and relapsing infections. They are thus important drivers of increased morbidity and mortality rates resulting in growing healthcare costs. Antibiotic resistance is readily identifiable with standard microbiological assays, and the threat imposed by antibiotic resistance has been well recognized. Measures aiming to reduce resistance development and spreading of resistant bacteria are being enforced. However, the phenomenon of bacteria surviving antibiotic exposure despite being fully susceptible, so-called antibiotic persistence, is still largely underestimated. In contrast to antibiotic resistance, antibiotic persistence is difficult to measure and therefore often missed, potentially leading to treatment failures. In this review, we focus on bacterial mechanisms allowing evasion of antibiotic killing and discuss their implications on human health. We describe the relationship between antibiotic persistence and bacterial heterogeneity and discuss recent studies that link bacterial persistence and tolerance with the evolution of antibiotic resistance. Finally, we review persister detection methods, novel strategies aiming at eradicating bacterial persisters and the latest advances in the development of new antibiotics.
Topics: Anti-Bacterial Agents; Bacteria; Drug Resistance, Bacterial; Drug Resistance, Microbial; Humans
PubMed: 33400359
DOI: 10.15252/embr.202051034 -
Nature Reviews. Microbiology May 2022Antibiotic resistance is a global health challenge, involving the transfer of bacteria and genes between humans, animals and the environment. Although multiple barriers... (Review)
Review
Antibiotic resistance is a global health challenge, involving the transfer of bacteria and genes between humans, animals and the environment. Although multiple barriers restrict the flow of both bacteria and genes, pathogens recurrently acquire new resistance factors from other species, thereby reducing our ability to prevent and treat bacterial infections. Evolutionary events that lead to the emergence of new resistance factors in pathogens are rare and challenging to predict, but may be associated with vast ramifications. Transmission events of already widespread resistant strains are, on the other hand, common, quantifiable and more predictable, but the consequences of each event are limited. Quantifying the pathways and identifying the drivers of and bottlenecks for environmental evolution and transmission of antibiotic resistance are key components to understand and manage the resistance crisis as a whole. In this Review, we present our current understanding of the roles of the environment, including antibiotic pollution, in resistance evolution, in transmission and as a mere reflection of the regional antibiotic resistance situation in the clinic. We provide a perspective on current evidence, describe risk scenarios, discuss methods for surveillance and the assessment of potential drivers, and finally identify some actions to mitigate risks.
Topics: Animals; Anti-Bacterial Agents; Bacteria; Bacterial Infections; Drug Resistance, Bacterial; Drug Resistance, Microbial
PubMed: 34737424
DOI: 10.1038/s41579-021-00649-x -
Nature Nov 2019The problem of resistance to therapy in cancer is multifaceted. Here we take a reductionist approach to define and separate the key determinants of drug resistance,... (Review)
Review
The problem of resistance to therapy in cancer is multifaceted. Here we take a reductionist approach to define and separate the key determinants of drug resistance, which include tumour burden and growth kinetics; tumour heterogeneity; physical barriers; the immune system and the microenvironment; undruggable cancer drivers; and the many consequences of applying therapeutic pressures. We propose four general solutions to drug resistance that are based on earlier detection of tumours permitting cancer interception; adaptive monitoring during therapy; the addition of novel drugs and improved pharmacological principles that result in deeper responses; and the identification of cancer cell dependencies by high-throughput synthetic lethality screens, integration of clinico-genomic data and computational modelling. These different approaches could eventually be synthesized for each tumour at any decision point and used to inform the choice of therapy.
Topics: Antineoplastic Agents; Drug Resistance, Neoplasm; Humans; Models, Biological; Neoplasms; Tumor Microenvironment
PubMed: 31723286
DOI: 10.1038/s41586-019-1730-1 -
Brazilian Journal of Microbiology :... Dec 2021The assembly of microorganisms over a surface and their ability to develop resistance against available antibiotics are major concerns of interest. To survive against... (Review)
Review
The assembly of microorganisms over a surface and their ability to develop resistance against available antibiotics are major concerns of interest. To survive against harsh environmental conditions including known antibiotics, the microorganisms form a unique structure, referred to as biofilm. The mechanism of biofilm formation is triggered and regulated by quorum sensing, hostile environmental conditions, nutrient availability, hydrodynamic conditions, cell-to-cell communication, signaling cascades, and secondary messengers. Antibiotic resistance, escape of microbes from the body's immune system, recalcitrant infections, biofilm-associated deaths, and food spoilage are some of the problems associated with microbial biofilms which pose a threat to humans, veterinary, and food processing sectors. In this review, we focus in detail on biofilm formation, its architecture, composition, genes and signaling cascades involved, and multifold antibiotic resistance exhibited by microorganisms dwelling within biofilms. We also highlight different physical, chemical, and biological biofilm control strategies including those based on plant products. So, this review aims at providing researchers the knowledge regarding recent advances on the mechanisms involved in biofilm formation at the molecular level as well as the emergent method used to get rid of antibiotic-resistant and life-threatening biofilms.
Topics: Anti-Bacterial Agents; Bacterial Physiological Phenomena; Biofilms; Drug Resistance, Microbial; Quorum Sensing
PubMed: 34558029
DOI: 10.1007/s42770-021-00624-x -
International Journal of Molecular... May 2020Cancer is one of the main causes of death worldwide. Despite the significant development of methods of cancer healing during the past decades, chemotherapy still remains... (Review)
Review
Cancer is one of the main causes of death worldwide. Despite the significant development of methods of cancer healing during the past decades, chemotherapy still remains the main method for cancer treatment. Depending on the mechanism of action, commonly used chemotherapeutic agents can be divided into several classes (antimetabolites, alkylating agents, mitotic spindle inhibitors, topoisomerase inhibitors, and others). Multidrug resistance (MDR) is responsible for over 90% of deaths in cancer patients receiving traditional chemotherapeutics or novel targeted drugs. The mechanisms of MDR include elevated metabolism of xenobiotics, enhanced efflux of drugs, growth factors, increased DNA repair capacity, and genetic factors (gene mutations, amplifications, and epigenetic alterations). Rapidly increasing numbers of biomedical studies are focused on designing chemotherapeutics that are able to evade or reverse MDR. The aim of this review is not only to demonstrate the latest data on the mechanisms of cellular resistance to anticancer agents currently used in clinical treatment but also to present the mechanisms of action of novel potential antitumor drugs which have been designed to overcome these resistance mechanisms. Better understanding of the mechanisms of MDR and targets of novel chemotherapy agents should provide guidance for future research concerning new effective strategies in cancer treatment.
Topics: Animals; Antineoplastic Agents; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Neoplasms; Pharmacogenetics
PubMed: 32370233
DOI: 10.3390/ijms21093233 -
Biomedicine & Pharmacotherapy =... Apr 2020Cancer immunotherapy is an innovative treatment for tumors today. In various experiments and clinical studies, it has been found that immunotherapy does have... (Review)
Review
Cancer immunotherapy is an innovative treatment for tumors today. In various experiments and clinical studies, it has been found that immunotherapy does have incomparable advantages over traditional anti-tumor therapy, which can prolong progression-free survival (PFS) and overall survival (OS). However, immunotherapy has obvious complexity and uncertainty. Immunotherapy may also cause severe adverse reactions due to an overactive immune system. More effective and fewer adverse reactions immunological checkpoints are still under further exploration. This review gives an overview of recent developments in immunotherapy and indicates a new direction of tumor treatment through analyzing the pros and cons of immunotherapy coupled with keeping a close watch on the development trend of the immunotherapy future.
Topics: Antineoplastic Agents, Immunological; Drug Resistance; Humans; Immunotherapy; Immunotherapy, Adoptive; Killer Cells, Natural; Neoplasms
PubMed: 31962285
DOI: 10.1016/j.biopha.2020.109821 -
Frontiers in Cellular and Infection... 2022Both, antibiotic persistence and antibiotic resistance characterize phenotypes of survival in which a bacterial cell becomes insensitive to one (or even) more... (Review)
Review
Both, antibiotic persistence and antibiotic resistance characterize phenotypes of survival in which a bacterial cell becomes insensitive to one (or even) more antibiotic(s). However, the molecular basis for these two antibiotic-tolerant phenotypes is fundamentally different. Whereas antibiotic resistance is genetically determined and hence represents a rather stable phenotype, antibiotic persistence marks a transient physiological state triggered by various stress-inducing conditions that switches back to the original antibiotic sensitive state once the environmental situation improves. The molecular basics of antibiotic resistance are in principle well understood. This is not the case for antibiotic persistence. Under all culture conditions, there is a stochastically formed, subpopulation of persister cells in bacterial populations, the size of which depends on the culture conditions. The proportion of persisters in a bacterial population increases under different stress conditions, including treatment with bactericidal antibiotics (BCAs). Various models have been proposed to explain the formation of persistence in bacteria. We recently hypothesized that all physiological culture conditions leading to persistence converge in the inability of the bacteria to re-initiate a new round of DNA replication caused by an insufficient level of the initiator complex ATP-DnaA and hence by the lack of formation of a functional orisome. Here, we extend this hypothesis by proposing that in this persistence state the bacteria become more susceptible to mutation-based antibiotic resistance provided they are equipped with error-prone DNA repair functions. This is - in our opinion - in particular the case when such bacterial populations are exposed to BCAs.
Topics: Anti-Bacterial Agents; Bacteria; Drug Resistance, Bacterial; Drug Resistance, Microbial
PubMed: 35928205
DOI: 10.3389/fcimb.2022.900848 -
Journal of Molecular Biology Aug 2019The biosynthesis of antibiotics and self-protection mechanisms employed by antibiotic producers are an integral part of the growing antibiotic resistance threat. The... (Review)
Review
The biosynthesis of antibiotics and self-protection mechanisms employed by antibiotic producers are an integral part of the growing antibiotic resistance threat. The origins of clinically relevant antibiotic resistance genes found in human pathogens have been traced to ancient microbial producers of antibiotics in natural environments. Widespread and frequent antibiotic use amplifies environmental pools of antibiotic resistance genes and increases the likelihood for the selection of a resistance event in human pathogens. This perspective will provide an overview of the origins of antibiotic resistance to highlight the crossroads of antibiotic biosynthesis and producer self-protection that result in clinically relevant resistance mechanisms. Some case studies of synergistic antibiotic combinations, adjuvants, and hybrid antibiotics will also be presented to show how native antibiotic producers manage the emergence of antibiotic resistance.
Topics: Animals; Anti-Bacterial Agents; Bacteria; Biological Evolution; Biological Products; Carrier Proteins; Drug Combinations; Drug Discovery; Drug Resistance, Microbial; Drug Synergism; Environment; Humans; Kinetics; Metagenomics; Thermodynamics
PubMed: 31288031
DOI: 10.1016/j.jmb.2019.06.033 -
Chemical Reviews Mar 2021
Topics: Anti-Infective Agents; Antineoplastic Agents; Drug Evaluation, Preclinical; Drug Resistance; Herbicides; Humans; Pesticides; Protein Binding; Signal Transduction; Structure-Activity Relationship
PubMed: 33757288
DOI: 10.1021/acs.chemrev.1c00118 -
Drug Resistance Updates : Reviews and... Mar 2020Lipids, phospholipids and cholesterol in particular, are the predominant components of the plasma membrane, wherein multidrug efflux transporters of the ATP-binding... (Review)
Review
Lipids, phospholipids and cholesterol in particular, are the predominant components of the plasma membrane, wherein multidrug efflux transporters of the ATP-binding cassette (ABC) superfamily reside as integral pump proteins. In the current review, we discuss how lipids potently modulate the expression and activity of these multidrug efflux pumps, contributing to the development of the multidrug resistance (MDR) phenotype in cancer. The molecular mechanisms underlying this modulation of the MDR phenotype are pleiotropic. First, notwithstanding the high intra-and inter-tumor variability, MDR cells display an altered composition of plasma membrane phospholipids and glycosphingolipids, and are enriched with very long saturated fatty acid chains. This feature, along with the increased levels of cholesterol, decrease membrane fluidity, alter the spatial organization of membrane nano- and micro-domains, interact with transmembrane helices of ABC transporters, hence favoring drug binding and release. Second, MDR cells exhibit a peculiar membrane lipid composition of intracellular organelles including mitochondria and endoplasmic reticulum (ER). In this respect, they contain a lower amount of oxidizable fatty acids, hence being more resistant to oxidative stress and chemotherapy-induced apoptosis. Third, drug resistant cancer cells have a higher ratio of monosatured/polyunsatured fatty acids: this lipid signature reduces the production of reactive aldehydes with cytotoxic and pro-inflammatory activity and, together with the increased activity of anti-oxidant enzymes, limits the cellular damage induced by lipid peroxidation. Finally, specific precursors of phospholipids and cholesterol including ceramides and isoprenoids, are highly produced in MDR cells; by acting as second messengers, they trigger multiple signaling cascades that induce the transcription of drug efflux transporter genes and/or promote a metabolic reprogramming which supports the MDR phenotype. High-throughput lipidomics and computational biology technologies are a great tool in analyzing the tumor lipid signature in a personalized manner and in identifying novel biomarkers of drug resistance. Moreover, beyond the induction of MDR, lipid metabolism offers a remarkable opportunity to reverse MDR by using lipid analogues and repurposing lipid-targeting drugs (e.g. statins and aminobisphosphonates) that reprogram the lipid composition of drug resistant cells, hence rendering them drug sensitive.
Topics: Antineoplastic Agents; Cell Membrane; Cholesterol; Drug Resistance, Multiple; Drug Resistance, Neoplasm; High-Throughput Screening Assays; Humans; Neoplasms; Phospholipids
PubMed: 31846838
DOI: 10.1016/j.drup.2019.100670