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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 -
Theranostics 2021Antimicrobial resistance has been a global health challenge that threatens our ability to control and treat life-threatening bacterial infections. Despite ongoing... (Review)
Review
Antimicrobial resistance has been a global health challenge that threatens our ability to control and treat life-threatening bacterial infections. Despite ongoing efforts to identify new drugs or alternatives to antibiotics, no new classes of antibiotic or their alternatives have been clinically approved in the last three decades. A combination of antibiotics and non-antibiotic compounds that could inhibit bacterial resistance determinants or enhance antibiotic activity offers a sustainable and effective strategy to confront multidrug-resistant bacteria. In this review, we provide a brief overview of the co-evolution of antibiotic discovery and the development of bacterial resistance. We summarize drug-drug interactions and uncover the art of repurposing non-antibiotic drugs as potential antibiotic adjuvants, including discussing classification and mechanisms of action, as well as reporting novel screening platforms. A pathogen-by-pathogen approach is then proposed to highlight the critical value of drug repurposing and its therapeutic potential. Finally, general advantages, challenges and development trends of drug combination strategy are discussed.
Topics: Adjuvants, Pharmaceutic; Anti-Bacterial Agents; Bacterial Infections; Drug Interactions; Drug Repositioning; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial; Drug Synergism; Drug Therapy, Combination; Humans
PubMed: 33754035
DOI: 10.7150/thno.56205 -
The Yale Journal of Biology and Medicine Mar 2017Undoubtedly, the discovery of penicillin is one of the greatest milestones in modern medicine. 2016 marks the 75th anniversary of the first systemic administration of... (Review)
Review
Undoubtedly, the discovery of penicillin is one of the greatest milestones in modern medicine. 2016 marks the 75th anniversary of the first systemic administration of penicillin in humans, and is therefore an occasion to reflect upon the extraordinary impact that penicillin has had on the lives of millions of people since. This perspective presents a historical account of the discovery of the wonder drug, describes the biological nature of penicillin, and considers lessons that can be learned from the golden era of antibiotic research, which took place between the 1940s and 1960s. Looking back at the history of penicillin might help us to relive this journey to find new treatments and antimicrobial agents. This is particularly relevant today as the emergence of multiple drug resistant bacteria poses a global threat, and joint efforts are needed to combat the rise and spread of resistance.
Topics: Anti-Bacterial Agents; Anti-Infective Agents; Drug Resistance, Microbial; Drug Resistance, Multiple, Bacterial; Humans; Penicillins
PubMed: 28356901
DOI: No ID Found -
Molecules (Basel, Switzerland) Jan 2022Multidrug resistance is a leading concern in public health. It describes a complex phenotype whose predominant feature is resistance to a wide range of structurally... (Review)
Review
Multidrug resistance is a leading concern in public health. It describes a complex phenotype whose predominant feature is resistance to a wide range of structurally unrelated cytotoxic compounds, many of which are anticancer agents. Multidrug resistance may be also related to antimicrobial drugs, and is known to be one of the most serious global public health threats of this century. Indeed, this phenomenon has increased both mortality and morbidity as a consequence of treatment failures and its incidence in healthcare costs. The large amounts of antibiotics used in human therapies, as well as for farm animals and even for fishes in aquaculture, resulted in the selection of pathogenic bacteria resistant to multiple drugs. It is not negligible that the ongoing COVID-19 pandemic may further contribute to antimicrobial resistance. In this paper, multidrug resistance and antimicrobial resistance are underlined, focusing on the therapeutic options to overcome these obstacles in drug treatments. Lastly, some recent studies on nanodrug delivery systems have been reviewed since they may represent a significant approach for overcoming resistance.
Topics: Animals; Drug Resistance, Microbial; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Nanoparticle Drug Delivery System
PubMed: 35163878
DOI: 10.3390/molecules27030616 -
International Microbiology : the... Nov 2021We are living in a society of fear, where the objectivity in estimating risks is distorted by the media and the interested parties. During more than half of a century,... (Review)
Review
We are living in a society of fear, where the objectivity in estimating risks is distorted by the media and the interested parties. During more than half of a century, the feeling of antibiotic resistance as an apocalyptic phenomenon able to push our society to the high mortality rates caused by infectious diseases in the dark pre-antibiotic ages has been steadily rising. However, at the current status of modern medicine, at least in the high-medium income countries, mortality by lack of efficacy of the antibiotic armamentarium in the therapy of infections is a problem, but not a catastrophe. The threat of antibiotic resistance has many other aspects than failures of therapy in the individual patient. Among them, the increase in the frequency of severe and potentially lethal infections, as bacteremia, the population biology alterations of the healthy microbiota, the global acceleration of bacterial evolution by selecting natural genetic tools mediating microbial interactions, and, most importantly, by modifying the equilibrium and composition of environmental microbial communities. All these threats have huge implications for human health as members of a Biosphere entirely rooted in a menaced microbiosphere.
Topics: Anti-Bacterial Agents; Bacteria; Drug Resistance, Bacterial; Drug Resistance, Microbial; Humans; Microbiota
PubMed: 34028624
DOI: 10.1007/s10123-021-00184-y -
Microbiology Spectrum Dec 2017The increase in bacteria harboring antimicrobial resistance (AMR) is a global problem because there is a paucity of antibiotics available to treat multidrug-resistant... (Review)
Review
The increase in bacteria harboring antimicrobial resistance (AMR) is a global problem because there is a paucity of antibiotics available to treat multidrug-resistant bacterial infections in humans and animals. Detection of AMR present in bacteria that may pose a threat to veterinary and public health is routinely performed using standardized phenotypic methods. Molecular methods are often used in addition to phenotypic methods but are set to replace them in many laboratories due to the greater speed and accuracy they provide in detecting the underlying genetic mechanism(s) for AMR. In this article we describe some of the common molecular methods currently used for detection of AMR genes. These include PCR, DNA microarray, whole-genome sequencing and metagenomics, and matrix-assisted laser desorption ionization-time of flight mass spectrometry. The strengths and weaknesses of these methods are discussed, especially in the context of implementing them for routine surveillance activities on a global scale for mitigating the risk posed by AMR worldwide. Based on current popularity and ease of use, PCR and single-isolate whole-genome sequencing seem irreplaceable.
Topics: Animals; Anti-Bacterial Agents; Bacteria; Bacteriological Techniques; DNA, Bacterial; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial; Genetic Techniques; Humans; Metagenomics; Oligonucleotide Array Sequence Analysis; Polymerase Chain Reaction; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Whole Genome Sequencing
PubMed: 29219107
DOI: 10.1128/microbiolspec.ARBA-0011-2017 -
Molecular Microbiology May 2022
Topics: Anti-Bacterial Agents; Drug Resistance, Bacterial; Microbial Sensitivity Tests
PubMed: 35621028
DOI: 10.1111/mmi.14912 -
Current Opinion in Structural Biology Feb 2023Robust technology has been developed to systematically quantify fitness landscapes that provide valuable opportunities to improve our understanding of drug resistance... (Review)
Review
Robust technology has been developed to systematically quantify fitness landscapes that provide valuable opportunities to improve our understanding of drug resistance and define new avenues to develop drugs with reduced resistance susceptibility. We outline the critical importance of drug resistance studies and the potential for fitness landscape approaches to contribute to this effort. We describe the major technical advancements in mutational scanning, which is the primary approach used to quantify protein fitness landscapes. There are many complex steps to consider in planning and executing mutational scanning projects including developing a selection scheme, generating mutant libraries, tracking the frequency of variants using next-generation sequencing, and processing and interpreting the data. Key experimental parameters impacting each of these steps are discussed to aid in planning fitness landscape studies. There is a strong need for improved understanding of drug resistance, and fitness landscapes provide a promising new approach.
Topics: Genetic Fitness; Models, Genetic; Mutation; Proteins; Drug Resistance
PubMed: 36621152
DOI: 10.1016/j.sbi.2022.102525 -
Gut Microbes 2023poses a serious threat to public health and socioeconomic development worldwide because of its foodborne pathogenicity and antimicrobial resistance. This... (Review)
Review
poses a serious threat to public health and socioeconomic development worldwide because of its foodborne pathogenicity and antimicrobial resistance. This biofilm-planktonic lifestyle enables to interfere with the host and become resistant to drugs, conferring inherent tolerance to antibiotics. The complex biofilm structure makes bacteria tolerant to harsh conditions due to the diversity of physiological, biochemical, environmental, and molecular factors constituting resistance mechanisms. Here, we provide an overview of the mechanisms of biofilm formation and antibiotic resistance, with an emphasis on less-studied molecular factors and in-depth analysis of the latest knowledge about upregulated drug-resistance-associated genes in bacterial aggregates. We classified and extensively discussed each group of these genes encoding transporters, outer membrane proteins, enzymes, multiple resistance, metabolism, and stress response-associated proteins. Finally, we highlighted the missing information and studies that need to be undertaken to understand biofilm features and contribute to eliminating antibiotic-resistant and health-threatening biofilms.
Topics: Gastrointestinal Microbiome; Biofilms; Drug Resistance, Microbial; Anti-Bacterial Agents; Salmonella; Drug Resistance, Bacterial
PubMed: 37401756
DOI: 10.1080/19490976.2023.2229937