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The FEBS Journal Oct 2020Drug-resistant bacterial infections have led to a global health crisis. Although much effort is placed on the development of new antibiotics or variants that are less... (Review)
Review
Drug-resistant bacterial infections have led to a global health crisis. Although much effort is placed on the development of new antibiotics or variants that are less subject to existing resistance mechanisms, history shows that this strategy by itself is unlikely to solve the problem of drug resistance. Here, we discuss inhibiting evolution as a strategy that, in combination with antibiotics, may resolve the problem. Although mutagenesis is the main driver of drug resistance development, attacking the drivers of genetic diversification in pathogens has not been well explored. Bacteria possess active mechanisms that increase the rate of mutagenesis, especially at times of stress, such as during replication within eukaryotic host cells, or exposure to antibiotics. We highlight how the existence of these promutagenic proteins (evolvability factors) presents an opportunity that can be capitalized upon for the effective inhibition of drug resistance development. To help move this idea from concept to execution, we first describe a set of criteria that an 'optimal' evolvability factor would likely have to meet to be a viable therapeutic target. We then discuss the intricacies of some of the known mutagenic mechanisms and evaluate their potential as drug targets to inhibit evolution. In principle, and as suggested by recent studies, we argue that the inhibition of these and other evolvability factors should reduce resistance development. Finally, we discuss the challenges of transitioning anti-evolution drugs from the laboratory to the clinic.
Topics: Anti-Bacterial Agents; Bacterial Infections; Drug Resistance, Bacterial
PubMed: 32434280
DOI: 10.1111/febs.15370 -
Trends in Cell Biology Apr 2015Interactions between cancer cells and their surroundings can trigger essential signaling cues that determine cell fate and influence the evolution of the malignant... (Review)
Review
Interactions between cancer cells and their surroundings can trigger essential signaling cues that determine cell fate and influence the evolution of the malignant phenotype. As the primary receptors involved in cell-matrix adhesion, integrins present on the surface of tumor and stromal cells have a profound impact on the ability to survive in specific locations, but in some cases, these receptors can also function in the absence of ligand binding to promote stemness and survival in the presence of environmental and therapeutic stresses. Understanding how integrin expression and function is regulated in this context will enable the development of new therapeutic approaches to sensitize tumors to therapy and suppress their metastatic phenotype.
Topics: Cell Adhesion; Drug Resistance; Humans; Integrins; Neoplasm Metastasis; Neoplasms; Signal Transduction; Stem Cells; Stromal Cells
PubMed: 25572304
DOI: 10.1016/j.tcb.2014.12.006 -
Praxis Feb 2020
Topics: Anti-Bacterial Agents; Drug Resistance, Bacterial
PubMed: 32019456
DOI: 10.1024/1661-8157/a003414 -
Roczniki Panstwowego Zakladu Higieny 2019Candida spp. has been identified as the most common member of human gut microbiota. This yeast-like fungus is recognized as an opportunistic organism due to its...
BACKGROUND
Candida spp. has been identified as the most common member of human gut microbiota. This yeast-like fungus is recognized as an opportunistic organism due to its potential to cause diseases in all parts of the gastrointestinal tract.
OBJECTIVE
The aim of the study was to investigate the relationship between diet and health of the study participants and the presence of gastrointestinal Candida spp. Susceptibility of Candida to antifungal drugs was determined.
MATERIAL AND METHODS
Material comprised of oral swabs and fecal samples self-collected by the study participants. The participants filled in a nutritional questionnaire. A total of 30 people took part in the study, including 28 women and 2 men. The study was conducted in Wroclaw, Poland. Susceptibility of Candida to antifungal drugs was determined using Bio-Rad’s FUNGITEST™ Kit designed for the susceptibility testing of yeasts to six antifungal drugs.
RESULTS
In the group with negative Candida spp. cultures, healthier wheat flour substitutes were consumed significantly more frequently than in the group with positive Candida spp. cultures. Yellow cheeses and quark were eaten significantly more frequently in the group with negative Candida spp. cultures. No antifungal resistance was detected in the study group.
CONCLUSIONS
The increased consumption of purified wheat flour products was linked to the presence of gastrointestinal Candida spp. A higher consumption of cheese was observed in the group with negative Candida spp. cultures, which may indicate the inhibitory effect of saturated fatty acids on the growth of human Candida spp. Sensitivity of C. albicans to antifungal drugs may increase effectiveness of candidiasis treatment.
Topics: Adult; Antifungal Agents; Colony Count, Microbial; Diet; Drug Resistance, Fungal; Drug Resistance, Microbial; Female; Gastrointestinal Tract; Humans; Male; Poland
PubMed: 31215785
DOI: 10.32394/rpzh.2019.0070 -
Molecular Medicine Reports Apr 2020Epilepsy is a common, serious neurological disorder worldwide. Although this disease can be successfully treated in most cases, not all patients respond favorably to... (Review)
Review
Epilepsy is a common, serious neurological disorder worldwide. Although this disease can be successfully treated in most cases, not all patients respond favorably to medical treatments, which can lead to pharmacoresistant epilepsy. Drug‑resistant epilepsy can be caused by a number of mechanisms that may involve environmental and genetic factors, as well as disease‑ and drug‑related factors. In recent years, numerous studies have demonstrated that genetic variation is involved in the drug resistance of epilepsy, especially genetic variations found in drug resistance‑related genes, including the voltage‑dependent sodium and potassium channels genes, and the metabolizer of endogenous and xenobiotic substances genes. The present review aimed to highlight the genetic variants that are involved in the regulation of drug resistance in epilepsy; a comprehensive understanding of the role of genetic variation in drug resistance will help us develop improved strategies to regulate drug resistance efficiently and determine the pathophysiological processes that underlie this common human neurological disease.
Topics: Drug Resistance; Epilepsy; Genetic Variation; Humans
PubMed: 32319641
DOI: 10.3892/mmr.2020.10999 -
Journal of Nanobiotechnology Sep 2022Cancer often develops multidrug resistance (MDR) when cancer cells become resistant to numerous structurally and functionally different chemotherapeutic agents. MDR is... (Review)
Review
Cancer often develops multidrug resistance (MDR) when cancer cells become resistant to numerous structurally and functionally different chemotherapeutic agents. MDR is considered one of the principal reasons for the failure of many forms of clinical chemotherapy. Several factors are involved in the development of MDR including increased expression of efflux transporters, the tumor microenvironment, changes in molecular targets and the activity of cancer stem cells. Recently, researchers have designed and developed a number of small molecule inhibitors and derivatives of natural compounds to overcome various mechanisms of clinical MDR. Unfortunately, most of the chemosensitizing approaches have failed in clinical trials due to non-specific interactions and adverse side effects at pharmacologically effective concentrations. Nanomedicine approaches provide an efficient drug delivery platform to overcome the limitations of conventional chemotherapy and improve therapeutic effectiveness. Multifunctional nanomaterials have been found to facilitate drug delivery by improving bioavailability and pharmacokinetics, enhancing the therapeutic efficacy of chemotherapeutic drugs to overcome MDR. In this review article, we discuss the major factors contributing to MDR and the limitations of existing chemotherapy- and nanocarrier-based drug delivery systems to overcome clinical MDR mechanisms. We critically review recent nanotechnology-based approaches to combat tumor heterogeneity, drug efflux mechanisms, DNA repair and apoptotic machineries to overcome clinical MDR. Recent successful therapies of this nature include liposomal nanoformulations, cRGDY-PEG-Cy5.5-Carbon dots and Cds/ZnS core-shell quantum dots that have been employed for the effective treatment of various cancer sub-types including small cell lung, head and neck and breast cancers.
Topics: Antineoplastic Agents; Carbon; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Nanotechnology; Neoplasms; Tumor Microenvironment
PubMed: 36153528
DOI: 10.1186/s12951-022-01626-z -
Parasitology International Dec 2022Genetic mapping has been widely employed to search for genes linked to phenotypes/traits of interest. Because of the ease of maintaining rodent malaria parasites in... (Review)
Review
Genetic mapping has been widely employed to search for genes linked to phenotypes/traits of interest. Because of the ease of maintaining rodent malaria parasites in laboratory mice, many genetic crosses of rodent malaria parasites have been performed to map the parasite genes contributing to malaria parasite development, drug resistance, host immune response, and disease pathogenesis. Drs. Richard Carter, David Walliker, and colleagues at the University of Edinburgh, UK, were the pioneers in developing the systems for genetic mapping of malaria parasite traits, including characterization of genetic markers to follow the inheritance and recombination of parasite chromosomes and performing the first genetic cross using rodent malaria parasites. Additionally, many genetic crosses of inbred mice have been performed to link mouse chromosomal loci to the susceptibility to malaria parasite infections. In this chapter, we review and discuss past and recent advances in genetic marker development, performing genetic crosses, and genetic mapping of both parasite and host genes. Genetic mappings using models of rodent malaria parasites and inbred mice have contributed greatly to our understanding of malaria, including parasite development within their hosts, mechanism of drug resistance, and host-parasite interaction.
Topics: Animals; Disease Susceptibility; Drug Resistance; Genetic Markers; Malaria; Mice; Parasites; Rodentia; Virulence
PubMed: 35926693
DOI: 10.1016/j.parint.2022.102637 -
Drug Delivery and Translational Research Jun 2024Antimicrobial resistance and tolerance (AMR&T) are urgent global health concerns, with alarmingly increasing numbers of antimicrobial drugs failing and a corresponding... (Review)
Review
Antimicrobial resistance and tolerance (AMR&T) are urgent global health concerns, with alarmingly increasing numbers of antimicrobial drugs failing and a corresponding rise in related deaths. Several reasons for this situation can be cited, such as the misuse of traditional antibiotics, the massive use of sanitizing measures, and the overuse of antibiotics in agriculture, fisheries, and cattle. AMR&T management requires a multifaceted approach involving various strategies at different levels, such as increasing the patient's awareness of the situation and measures to reduce new resistances, reduction of current misuse or abuse, and improvement of selectivity of treatments. Also, the identification of new antibiotics, including small molecules and more complex approaches, is a key factor. Among these, novel DNA- or RNA-based approaches, the use of phages, or CRISPR technologies are some potent strategies under development. In this perspective article, emerging and experienced leaders in drug delivery discuss the most important biological barriers for drugs to reach infectious bacteria (bacterial bioavailability). They explore how overcoming these barriers is crucial for producing the desired effects and discuss the ways in which drug delivery systems can facilitate this process.
Topics: Humans; Anti-Bacterial Agents; Drug Delivery Systems; Animals; Drug Resistance, Microbial; Drug Resistance, Bacterial; Bacteria; Drug Tolerance
PubMed: 38341386
DOI: 10.1007/s13346-023-01513-6 -
Biomedicine & Pharmacotherapy =... Jul 2020Chemotherapy and targeted therapy can significantly improve survival rates in cancer, but multiple drug resistance (MDR) limits the efficacy of these approaches.... (Review)
Review
Chemotherapy and targeted therapy can significantly improve survival rates in cancer, but multiple drug resistance (MDR) limits the efficacy of these approaches. Understanding the molecular mechanisms underlying MDR is crucial for improving drug efficacy and clinical outcomes of patients with cancer. S100 proteins belong to a family of calcium-binding proteins and have various functions in tumor development. Increasing evidence demonstrates that the dysregulation of various S100 proteins contributes to the development of drug resistance in tumors, providing a basis for the development of predictive and prognostic biomarkers in cancer. Therefore, a combination of biological inhibitors or sensitizers of dysregulated S100 proteins could enhance therapeutic responses. In this review, we provide a detailed overview of the mechanisms by which S100 family members influence resistance of tumors to cancer treatment, with a focus on the development of effective strategies for overcoming MDR.
Topics: Animals; Antineoplastic Agents; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Molecular Targeted Therapy; Neoplasms; S100 Proteins
PubMed: 32335300
DOI: 10.1016/j.biopha.2020.110156 -
Drug Development Research Feb 2019The relentless rise of antibiotic resistance is considered one of the most serious problems facing mankind. This mini-review will cover three cutting-edge approaches... (Review)
Review
The relentless rise of antibiotic resistance is considered one of the most serious problems facing mankind. This mini-review will cover three cutting-edge approaches that use light-based techniques to kill antibiotic-resistant microbial species, and treat localized infections. First, we will discuss antimicrobial photodynamic inactivation using rationally designed photosensitizes combined with visible light, with the added possibility of strong potentiation by inorganic salts such as potassium iodide. Second, the use of blue and violet light alone that activates endogenous photoactive porphyrins within the microbial cells. Third, it is used for "safe UVC" at wavelengths between 200 nm and 230 nm that can kill microbial cells without damaging host mammalian cells. We have gained evidence that all these approaches can kill multidrug resistant bacteria in vitro, and they do not induce themselves any resistance, and moreover can treat animal models of localized infections caused by resistant species that can be monitored by noninvasive bioluminescence imaging. Light-based antimicrobial approaches are becoming a growing translational part of anti-infective treatments in the current age of resistance.
Topics: Animals; Anti-Bacterial Agents; Drug Resistance, Bacterial; Electromagnetic Fields; Humans; Light; Photochemotherapy; Photosensitizing Agents
PubMed: 30070718
DOI: 10.1002/ddr.21453