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Nature Reviews. Microbiology Aug 2023Throughout their evolutionary history, bacteria have faced diverse threats from other microorganisms, including competing bacteria, bacteriophages and predators. In... (Review)
Review
Throughout their evolutionary history, bacteria have faced diverse threats from other microorganisms, including competing bacteria, bacteriophages and predators. In response to these threats, they have evolved sophisticated defence mechanisms that today also protect bacteria against antibiotics and other therapies. In this Review, we explore the protective strategies of bacteria, including the mechanisms, evolution and clinical implications of these ancient defences. We also review the countermeasures that attackers have evolved to overcome bacterial defences. We argue that understanding how bacteria defend themselves in nature is important for the development of new therapies and for minimizing resistance evolution.
Topics: Anti-Bacterial Agents; Drug Resistance, Bacterial; Bacteria; Bacteriophages
PubMed: 37095190
DOI: 10.1038/s41579-023-00877-3 -
Nature Aug 2023Even among genetically identical cancer cells, resistance to therapy frequently emerges from a small subset of those cells. Molecular differences in rare individual...
Even among genetically identical cancer cells, resistance to therapy frequently emerges from a small subset of those cells. Molecular differences in rare individual cells in the initial population enable certain cells to become resistant to therapy; however, comparatively little is known about the variability in the resistance outcomes. Here we develop and apply FateMap, a framework that combines DNA barcoding with single-cell RNA sequencing, to reveal the fates of hundreds of thousands of clones exposed to anti-cancer therapies. We show that resistant clones emerging from single-cell-derived cancer cells adopt molecularly, morphologically and functionally distinct resistant types. These resistant types are largely predetermined by molecular differences between cells before drug addition and not by extrinsic factors. Changes in the dose and type of drug can switch the resistant type of an initial cell, resulting in the generation and elimination of certain resistant types. Samples from patients show evidence for the existence of these resistant types in a clinical context. We observed diversity in resistant types across several single-cell-derived cancer cell lines and cell types treated with a variety of drugs. The diversity of resistant types as a result of the variability in intrinsic cell states may be a generic feature of responses to external cues.
Topics: Humans; Clone Cells; DNA Barcoding, Taxonomic; Drug Resistance, Neoplasm; Neoplasms; RNA-Seq; Single-Cell Gene Expression Analysis; Tumor Cells, Cultured; Antineoplastic Agents
PubMed: 37468627
DOI: 10.1038/s41586-023-06342-8 -
Nature Reviews. Cancer Nov 2023Cancer cells frequently display intrinsic or acquired resistance to chemically diverse anticancer drugs, limiting therapeutic success. Among the main mechanisms of this... (Review)
Review
Cancer cells frequently display intrinsic or acquired resistance to chemically diverse anticancer drugs, limiting therapeutic success. Among the main mechanisms of this multidrug resistance is the overexpression of ATP-binding cassette (ABC) transporters that mediate drug efflux, and, specifically, ABCB1, ABCG2 and ABCC1 are known to cause cancer chemoresistance. High-resolution structures, biophysical and in silico studies have led to tremendous progress in understanding the mechanism of drug transport by these ABC transporters, and several promising therapies, including irradiation-based immune and thermal therapies, and nanomedicine have been used to overcome ABC transporter-mediated cancer chemoresistance. In this Review, we highlight the progress achieved in the past 5 years on the three transporters, ABCB1, ABCG2 and ABCC1, that are known to be of clinical importance. We address the molecular basis of their broad substrate specificity gleaned from structural information and discuss novel approaches to block the function of ABC transporters. Furthermore, genetic modification of ABC transporters by CRISPR-Cas9 and approaches to re-engineer amino acid sequences to change the direction of transport from efflux to import are briefly discussed. We suggest that current information regarding the structure, mechanism and regulation of ABC transporters should be used in clinical trials to improve the efficiency of chemotherapeutics for patients with cancer.
Topics: Humans; ATP-Binding Cassette Transporters; Drug Resistance, Neoplasm; Drug Resistance, Multiple; Antineoplastic Agents
PubMed: 37714963
DOI: 10.1038/s41568-023-00612-3 -
Proceedings of the National Academy of... Aug 2023Microbes evolve rapidly by modifying their genomes through mutations or through the horizontal acquisition of mobile genetic elements (MGEs) linked with fitness traits...
Microbes evolve rapidly by modifying their genomes through mutations or through the horizontal acquisition of mobile genetic elements (MGEs) linked with fitness traits such as antimicrobial resistance (AMR), virulence, and metabolic functions. We conducted a multicentric study in India and collected different clinical samples for decoding the genome sequences of bacterial pathogens associated with sepsis, urinary tract infections, and respiratory infections to understand the functional potency associated with AMR and its dynamics. Genomic analysis identified several acquired AMR genes (ARGs) that have a pathogen-specific signature. We observed that , , , and (2) were prevalent in , and , , , , and were dominant in . In contrast, and harbored , , 3'), , , (3') variants, and , respectively. Regardless of the type of ARG, the MGEs linked with ARGs were also pathogen-specific. The sequence type of these pathogens was identified as high-risk international clones, with only a few lineages being predominant and region-specific. Whole-cell proteome analysis of extensively drug-resistant , and strains revealed differential abundances of resistance-associated proteins in the presence and absence of different classes of antibiotics. The pathogen-specific resistance signatures and differential abundance of AMR-associated proteins identified in this study should add value to AMR diagnostics and the choice of appropriate drug combinations for successful antimicrobial therapy.
Topics: Anti-Bacterial Agents; Escherichia coli; beta-Lactamases; Proteomics; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial; Klebsiella pneumoniae; Microbial Sensitivity Tests
PubMed: 37549252
DOI: 10.1073/pnas.2305465120 -
Cancer Letters Sep 2023Despite the remarkable clinical success of immunotherapy and molecular targeted therapy in patients with advanced tumors, chemotherapy remains the most commonly used... (Review)
Review
Despite the remarkable clinical success of immunotherapy and molecular targeted therapy in patients with advanced tumors, chemotherapy remains the most commonly used treatment for most tumor patients. Chemotherapy drugs effectively inhibit tumor cell proliferation and survival through their remarkable mechanisms. However, tumor cells often develop severe intrinsic and acquired chemoresistance under chemotherapy stress, limiting the effectiveness of chemotherapy and leading to treatment failure. Growing evidence suggests that alterations in lipid metabolism may be implicated in the development of chemoresistance in tumors. Therefore, in this review, we provide a comprehensive overview of fatty acid metabolism and its impact on chemoresistance mechanisms. Additionally, we discuss the potential of targeting fatty acid metabolism as a therapeutic strategy to overcome drug resistance.
Topics: Humans; Fatty Acids; Drug Resistance, Neoplasm; Neoplasms; Cell Proliferation; Immunotherapy
PubMed: 37597652
DOI: 10.1016/j.canlet.2023.216352 -
Revue de L'infirmiere Oct 2023
Topics: Humans; Drug Resistance, Microbial
PubMed: 37838362
DOI: 10.1016/j.revinf.2023.08.002 -
International Journal For Parasitology Jul 2023
Topics: Anthelmintics; Vaccines; Drug Resistance
PubMed: 37257805
DOI: 10.1016/j.ijpara.2023.05.004 -
Nature Reviews. Microbiology Jan 2024Antimicrobial resistance (AMR) poses a substantial threat to human health. The widespread prevalence of AMR is, in part, due to the horizontal transfer of antibiotic... (Review)
Review
Antimicrobial resistance (AMR) poses a substantial threat to human health. The widespread prevalence of AMR is, in part, due to the horizontal transfer of antibiotic resistance genes (ARGs), typically mediated by plasmids. Many of the plasmid-mediated resistance genes in pathogens originate from environmental, animal or human habitats. Despite evidence that plasmids mobilize ARGs between these habitats, we have a limited understanding of the ecological and evolutionary trajectories that facilitate the emergence of multidrug resistance (MDR) plasmids in clinical pathogens. One Health, a holistic framework, enables exploration of these knowledge gaps. In this Review, we provide an overview of how plasmids drive local and global AMR spread and link different habitats. We explore some of the emerging studies integrating an eco-evolutionary perspective, opening up a discussion about the factors that affect the ecology and evolution of plasmids in complex microbial communities. Specifically, we discuss how the emergence and persistence of MDR plasmids can be affected by varying selective conditions, spatial structure, environmental heterogeneity, temporal variation and coexistence with other members of the microbiome. These factors, along with others yet to be investigated, collectively determine the emergence and transfer of plasmid-mediated AMR within and between habitats at the local and global scale.
Topics: Animals; Humans; Anti-Bacterial Agents; Drug Resistance, Bacterial; One Health; Drug Resistance, Multiple; Plasmids
PubMed: 37430173
DOI: 10.1038/s41579-023-00926-x -
Trends in Microbiology Apr 2024Colistin is regarded as a last-line drug against serious infections caused by multidrug-resistant Gram-negative bacterial pathogens. Therefore, the emergence of mobile... (Review)
Review
Colistin is regarded as a last-line drug against serious infections caused by multidrug-resistant Gram-negative bacterial pathogens. Therefore, the emergence of mobile colistin resistance (mcr) genes has attracted global concern and led to policy changes for the use of colistin in food animals across many countries. Currently, the distribution, function, mechanism of action, transmission vehicles, origin of mcr, and new treatment strategies against MCR-producing pathogens have been extensively studied. Here we review the prevalence, structure and function of mcr, the fitness cost and persistence of mcr-carrying plasmids, the impact of MCR on host immune response, as well as the control strategies to combat mcr-mediated colistin resistance.
Topics: Animals; Colistin; Anti-Bacterial Agents; Drug Resistance, Bacterial; Plasmids; Drug Resistance, Multiple, Bacterial; Escherichia coli Proteins; Microbial Sensitivity Tests
PubMed: 38008597
DOI: 10.1016/j.tim.2023.10.006 -
Advanced Drug Delivery Reviews Jul 2023The growing occurrence of invasive fungal infections and the mounting rates of drug resistance constitute a significant menace to human health. Antifungal drug... (Review)
Review
The growing occurrence of invasive fungal infections and the mounting rates of drug resistance constitute a significant menace to human health. Antifungal drug combinations have garnered substantial interest for their potential to improve therapeutic efficacy, reduce drug doses, reverse, or ameliorate drug resistance. A thorough understanding of the molecular mechanisms underlying antifungal drug resistance and drug combination is key to developing new drug combinations. Here we discuss the mechanisms of antifungal drug resistance and elucidate how to discover potent drug combinations to surmount resistance. We also examine the challenges encountered in developing such combinations and discuss prospects, including advanced drug delivery strategies.
Topics: Humans; Antifungal Agents; Mycoses; Drug Combinations; Drug Resistance, Fungal
PubMed: 37211279
DOI: 10.1016/j.addr.2023.114874