# | Rank | Similarity | Title + Abs. | Year | PMID |
|---|---|---|---|---|---|
| 0 | 1 | 2 | 3 | 4 | 5 |
| 9550 | 0 | 1.0000 | Stereoselective Bacterial Metabolism of Antibiotics in Environmental Bacteria - A Novel Biochemical Workflow. Although molecular genetic approaches have greatly increased our understanding of the evolution and spread of antibiotic resistance genes, there are fewer studies on the dynamics of antibiotic - bacterial (A-B) interactions, especially with respect to stereochemistry. Addressing this knowledge gap requires an interdisciplinary synthesis, and the development of sensitive and selective analytical tools. Here we describe SAM (stereoselective antimicrobial metabolism) workflow, a novel interdisciplinary approach for assessing bacterial resistance mechanisms in the context of A-B interactions that utilise a combination of whole genome sequencing and mass spectrometry. Chloramphenicol was used to provide proof-of-concept to demonstrate the importance of stereoselective metabolism by resistant environmental bacteria. Our data shows that chloramphenicol can be stereoselectively transformed via microbial metabolism with R,R-(-)-CAP being subject to extensive metabolic transformation by an environmental bacterial strain. In contrast S,S-(+)-CAP is not metabolised by this bacterial strain, possibly due to the lack of previous exposure to this isomer in the absence of historical selective pressure to evolve metabolic capacity. | 2021 | 33935981 |
| 9564 | 1 | 0.9997 | Genomic tools to profile antibiotic mode of action. The increasing emergence of antimicrobial multiresistant bacteria is of great concern to public health. While these bacteria are becoming an ever more prominent cause of nosocomial and community-acquired infections worldwide, the antibiotic discovery pipeline has been stalled in the last few years with very few efforts in the research and development of novel antibacterial therapies. Some of the root causes that have hampered current antibiotic drug development are the lack of understanding of the mode of action (MOA) of novel antibiotic molecules and the poor characterization of the bacterial physiological response to antibiotics that ultimately causes resistance. Here, we review how bacterial genetic tools can be applied at the genomic level with the goal of profiling resistance to antibiotics and elucidating antibiotic MOAs. Specifically, we highlight how chemical genomic detection of the MOA of novel antibiotic molecules and antibiotic profiling by next-generation sequencing are leveraging basic antibiotic research to unprecedented levels with great opportunities for knowledge translation. | 2015 | 24617440 |
| 9597 | 2 | 0.9996 | Role of xenobiotic transporters in bacterial drug resistance and virulence. Since the discovery of antibiotic therapeutics, the battles between humans and infectious diseases have never been stopped. Humans always face the appearance of a new bacterial drug-resistant strain followed by new antibiotic development. However, as the genome sequences of infectious bacteria have been gradually determined, a completely new approach has opened. This approach can analyze the entire gene resources of bacterial drug resistance. Through analysis, it may be possible to discover the underlying mechanism of drug resistance that will appear in the future. In this review article, we will first introduce the method to analyze all the xenobiotic transporter genes by using the genomic information. Next, we will discuss the regulation of xenobiotic transporter gene expression through the two-component signal transduction system, the principal environmental sensing and response system in bacteria. Furthermore, we will also introduce the virulence roles of xenobiotic transporters, which is an ongoing research area. | 2008 | 18481812 |
| 9609 | 3 | 0.9996 | The classification of bacterial survival strategies in the presence of antimicrobials. The survival of bacteria under antibiotic therapy varies in nature and is based on the bacterial ability to employ a wide range of fundamentally different resistance mechanisms. This great diversity requires a disambiguation of the term 'resistance' and the development of a more precise classification of bacterial survival strategies during contact with antibiotics. The absence of a unified definition for the terms 'resistance', 'tolerance' and 'persistence' further aggravates the imperfections of the current classification system. This review suggests a number of original classification criteria that will take into account (1) the bacterial ability to replicate in the presence of antimicrobial agents, (2) existing evolutionary stability of a trait within a species, and (3) the presence or absence of specialized genes that determine the ability of a microorganism to decrease its own metabolism or switch it completely off. This review describes potential advantages of the suggested classification system, which include a better understanding of the relationship between bacterial survival in the presence of antibiotics and molecular mechanisms of cellular metabolism suppression, the opportunity to pinpoint targets to identify a true bacterial resistance profile. The true resistance profile in turn, could be used to develop effective diagnostic and antimicrobial therapy methods, while taking into consideration specific bacterial survival mechanisms. | 2021 | 33930413 |
| 9487 | 4 | 0.9996 | Molecular mechanisms of antibiotic resistance revisited. Antibiotic resistance is a global health emergency, with resistance detected to all antibiotics currently in clinical use and only a few novel drugs in the pipeline. Understanding the molecular mechanisms that bacteria use to resist the action of antimicrobials is critical to recognize global patterns of resistance and to improve the use of current drugs, as well as for the design of new drugs less susceptible to resistance development and novel strategies to combat resistance. In this Review, we explore recent advances in understanding how resistance genes contribute to the biology of the host, new structural details of relevant molecular events underpinning resistance, the identification of new resistance gene families and the interactions between different resistance mechanisms. Finally, we discuss how we can use this information to develop the next generation of antimicrobial therapies. | 2023 | 36411397 |
| 9436 | 5 | 0.9996 | Phenotypic Resistance to Antibiotics. The development of antibiotic resistance is usually associated with genetic changes, either to the acquisition of resistance genes, or to mutations in elements relevant for the activity of the antibiotic. However, in some situations resistance can be achieved without any genetic alteration; this is called phenotypic resistance. Non-inherited resistance is associated to specific processes such as growth in biofilms, a stationary growth phase or persistence. These situations might occur during infection but they are not usually considered in classical susceptibility tests at the clinical microbiology laboratories. Recent work has also shown that the susceptibility to antibiotics is highly dependent on the bacterial metabolism and that global metabolic regulators can modulate this phenotype. This modulation includes situations in which bacteria can be more resistant or more susceptible to antibiotics. Understanding these processes will thus help in establishing novel therapeutic approaches based on the actual susceptibility shown by bacteria during infection, which might differ from that determined in the laboratory. In this review, we discuss different examples of phenotypic resistance and the mechanisms that regulate the crosstalk between bacterial metabolism and the susceptibility to antibiotics. Finally, information on strategies currently under development for diminishing the phenotypic resistance to antibiotics of bacterial pathogens is presented. | 2013 | 27029301 |
| 9492 | 6 | 0.9996 | The Search for 'Evolution-Proof' Antibiotics. The effectiveness of antibiotics has been widely compromised by the evolution of resistance among pathogenic bacteria. It would be restored by the development of antibiotics to which bacteria cannot evolve resistance. We first discuss two kinds of 'evolution-proof' antibiotic. The first comprises literally evolution-proof antibiotics to which bacteria cannot become resistant by mutation or horizontal gene transfer. The second category comprises agents to which resistance may arise, but so rarely that it does not become epidemic. The likelihood that resistance to a novel agent will spread is evaluated here by a simple model that includes biological and therapeutic parameters governing the evolution of resistance within hosts and the transmission of resistant strains between hosts. This model leads to the conclusion that epidemic spread is unlikely if the frequency of mutations that confer resistance falls below a defined minimum value, and it identifies potential targets for intervention to prevent the evolution of resistance. Whether or not evolution-proof antibiotics are ever found, searching for them is likely to improve the deployment of new and existing agents by advancing our understanding of how resistance evolves. | 2018 | 29191398 |
| 9531 | 7 | 0.9996 | How to Evaluate Non-Growing Cells-Current Strategies for Determining Antimicrobial Resistance of VBNC Bacteria. Thanks to the achievements in sanitation, hygiene practices, and antibiotics, we have considerably improved in our ongoing battle against pathogenic bacteria. However, with our increasing knowledge about the complex bacterial lifestyles and cycles and their plethora of defense mechanisms, it is clear that the fight is far from over. One of these resistance mechanisms that has received increasing attention is the ability to enter a dormancy state termed viable but non-culturable (VBNC). Bacteria that enter the VBNC state, either through unfavorable environmental conditions or through potentially lethal stress, lose their ability to grow on standard enrichment media, but show a drastically increased tolerance against antimicrobials including antibiotics. The inability to utilize traditional culture-based methods represents a considerable experimental hurdle to investigate their increased antimicrobial resistance and impedes the development and evaluation of effective treatments or interventions against bacteria in the VBNC state. Although experimental approaches were developed to detect and quantify VBNCs, only a few have been utilized for antimicrobial resistance screening and this review aims to provide an overview of possible methodological approaches. | 2021 | 33530321 |
| 9608 | 8 | 0.9996 | A genome-wide atlas of antibiotic susceptibility targets and pathways to tolerance. Detailed knowledge on how bacteria evade antibiotics and eventually develop resistance could open avenues for novel therapeutics and diagnostics. It is thereby key to develop a comprehensive genome-wide understanding of how bacteria process antibiotic stress, and how modulation of the involved processes affects their ability to overcome said stress. Here we undertake a comprehensive genetic analysis of how the human pathogen Streptococcus pneumoniae responds to 20 antibiotics. We build a genome-wide atlas of drug susceptibility determinants and generated a genetic interaction network that connects cellular processes and genes of unknown function, which we show can be used as therapeutic targets. Pathway analysis reveals a genome-wide atlas of cellular processes that can make a bacterium less susceptible, and often tolerant, in an antibiotic specific manner. Importantly, modulation of these processes confers fitness benefits during active infections under antibiotic selection. Moreover, screening of sequenced clinical isolates demonstrates that mutations in genes that decrease antibiotic sensitivity and increase tolerance readily evolve and are frequently associated with resistant strains, indicating such mutations could be harbingers for the emergence of antibiotic resistance. | 2022 | 35672367 |
| 9671 | 9 | 0.9996 | Genome-scale genetic manipulation methods for exploring bacterial molecular biology. Bacteria are diverse and abundant, playing key roles in human health and disease, the environment, and biotechnology. Despite progress in genome sequencing and bioengineering, much remains unknown about the functional organization of prokaryotes. For instance, roughly a third of the protein-coding genes of the best-studied model bacterium, Escherichia coli, currently lack experimental annotations. Systems-level experimental approaches for investigating the functional associations of bacterial genes and genetic structures are essential for defining the fundamental molecular biology of microbes, preventing the spread of antibacterial resistance in the clinic, and driving the development of future biotechnological applications. This review highlights recently introduced large-scale genetic manipulation and screening procedures for the systematic exploration of bacterial gene functions, molecular relationships, and the global organization of bacteria at the gene, pathway, and genome levels. | 2012 | 22517266 |
| 9553 | 10 | 0.9996 | A machine learning framework to predict antibiotic resistance traits and yet unknown genes underlying resistance to specific antibiotics in bacterial strains. Recently, the frequency of observing bacterial strains without known genetic components underlying phenotypic resistance to antibiotics has increased. There are several strains of bacteria lacking known resistance genes; however, they demonstrate resistance phenotype to drugs of that family. Although such strains are fewer compared to the overall population, they pose grave emerging threats to an already heavily challenged area of antimicrobial resistance (AMR), where death tolls have reached ~700 000 per year and a grim projection of ~10 million deaths per year by 2050 looms. Considering the fact that development of novel antibiotics is not keeping pace with the emergence and dissemination of resistance, there is a pressing need to decipher yet unknown genetic mechanisms of resistance, which will enable developing strategies for the best use of available interventions and show the way for the development of new drugs. In this study, we present a machine learning framework to predict novel AMR factors that are potentially responsible for resistance to specific antimicrobial drugs. The machine learning framework utilizes whole-genome sequencing AMR genetic data and antimicrobial susceptibility testing phenotypic data to predict resistance phenotypes and rank AMR genes by their importance in discriminating the resistance from the susceptible phenotypes. In summary, we present here a bioinformatics framework for training machine learning models, evaluating their performances, selecting the best performing model(s) and finally predicting the most important AMR loci for the resistance involved. | 2021 | 34015806 |
| 9685 | 11 | 0.9996 | Biofilm: A Hotspot for Emerging Bacterial Genotypes. Bacteria have the ability to adapt to changing environments through rapid evolution mediated by modification of existing genetic information, as well as by horizontal gene transfer (HGT). This makes bacteria a highly successful life form when it comes to survival. Unfortunately, this genetic plasticity may result in emergence and dissemination of antimicrobial resistance and virulence genes, and even the creation of multiresistant "superbugs" which may pose serious threats to public health. As bacteria commonly reside in biofilms, there has been an increased interest in studying these phenomena within biofilms in recent years. This review summarizes the present knowledge within this important area of research. Studies on bacterial evolution in biofilms have shown that mature biofilms develop into diverse communities over time. There is growing evidence that the biofilm lifestyle may be more mutagenic than planktonic growth. Furthermore, all three main mechanisms for HGT have been observed in biofilms. This has been shown to occur both within and between bacterial species, and higher transfer rates in biofilms than in planktonic cultures were detected. Of special concern are the observations that mutants with increased antibiotic resistance occur at higher frequency in biofilms than in planktonic cultures even in the absence of antibiotic exposure. Likewise, efficient dissemination of antimicrobial resistance genes, as well as virulence genes, has been observed within the biofilm environment. This new knowledge emphasizes the importance of biofilm awareness and control. | 2018 | 29914658 |
| 9614 | 12 | 0.9996 | Antibiotic-Independent Adaptive Effects of Antibiotic Resistance Mutations. Antibiotic usage selects for the accumulation and spread of antibiotic-resistant bacteria. However, resistance can also accumulate in the absence of antibiotic exposure. Antibiotics are often designed to target widely distributed regulatory housekeeping genes. The targeting of such genes enables these antibiotics to be useful against a wider variety of pathogens. This review highlights work suggesting that regulatory housekeeping genes of the type targeted by many antibiotics function as hubs of adaptation to conditions unrelated to antibiotic exposure. As a result of this, some mutations to the regulatory housekeeping gene targets of antibiotics confer both antibiotic resistance and an adaptive effect unrelated to antibiotic exposure. Such antibiotic-independent adaptive effects of resistance mutations may substantially affect the dynamics of antibiotic resistance accumulation and spread. | 2017 | 28629950 |
| 9613 | 13 | 0.9996 | Using Selection by Nonantibiotic Stressors to Sensitize Bacteria to Antibiotics. Evolutionary adaptation of bacteria to nonantibiotic selective forces, such as osmotic stress, has been previously associated with increased antibiotic resistance, but much less is known about potentially sensitizing effects of nonantibiotic stressors. In this study, we use laboratory evolution to investigate adaptation of Enterococcus faecalis, an opportunistic bacterial pathogen, to a broad collection of environmental agents, ranging from antibiotics and biocides to extreme pH and osmotic stress. We find that nonantibiotic selection frequently leads to increased sensitivity to other conditions, including multiple antibiotics. Using population sequencing and whole-genome sequencing of single isolates from the evolved populations, we identify multiple mutations in genes previously linked with resistance to the selecting conditions, including genes corresponding to known drug targets or multidrug efflux systems previously tied to collateral sensitivity. Finally, we hypothesized based on the measured sensitivity profiles that sequential rounds of antibiotic and nonantibiotic selection may lead to hypersensitive populations by harnessing the orthogonal collateral effects of particular pairs of selective forces. To test this hypothesis, we show experimentally that populations evolved to a sequence of linezolid (an oxazolidinone antibiotic) and sodium benzoate (a common preservative) exhibit increased sensitivity to more stressors than adaptation to either condition alone. The results demonstrate how sequential adaptation to drug and nondrug environments can be used to sensitize bacteria to antibiotics and highlight new potential strategies for exploiting shared constraints governing adaptation to diverse environmental challenges. | 2020 | 31851309 |
| 9485 | 14 | 0.9996 | Evolution of Drug Resistance in Bacteria. Resistance to antibiotics is an important and timely problem of contemporary medicine. Rapid evolution of resistant bacteria calls for new preventive measures to slow down this process, and a longer-term progress cannot be achieved without a good understanding of the mechanisms through which drug resistance is acquired and spreads in microbial populations. Here, we discuss recent experimental and theoretical advances in our knowledge how the dynamics of microbial populations affects the evolution of antibiotic resistance . We focus on the role of spatial and temporal drug gradients and show that in certain situations bacteria can evolve de novo resistance within hours. We identify factors that lead to such rapid onset of resistance and discuss their relevance for bacterial infections. | 2016 | 27193537 |
| 9486 | 15 | 0.9996 | Acquired Bacterial Resistance to Antibiotics and Resistance Genes: From Past to Future. The discovery, commercialization, and regular administration of antimicrobial agents have revolutionized the therapeutic paradigm, making it possible to treat previously untreatable and fatal infections. However, the excessive use of antibiotics has led to develop resistance soon after their use in clinical practice, to the point of becoming a global emergency. The mechanisms of bacterial resistance to antibiotics are manifold, including mechanisms of destruction or inactivation, target site modification, or active efflux, and represent the main examples of evolutionary adaptation for the survival of bacterial species. The acquirement of new resistance mechanisms is a consequence of the great genetic plasticity of bacteria, which triggers specific responses that result in mutational adaptation, acquisition of genetic material, or alteration of gene expression, virtually producing resistance to all currently available antibiotics. Understanding resistance processes is critical to the development of new antimicrobial agents to counteract drug-resistant microorganisms. In this review, both the mechanisms of action of antibiotic resistance (AMR) and the antibiotic resistance genes (ARGs) mainly found in clinical and environmental bacteria will be reviewed. Furthermore, the evolutionary background of multidrug-resistant bacteria will be examined, and some promising elements to control or reduce the emergence and spread of AMR will be proposed. | 2025 | 40149034 |
| 9483 | 16 | 0.9996 | Ecological and evolutionary mechanisms driving within-patient emergence of antimicrobial resistance. The ecological and evolutionary mechanisms of antimicrobial resistance (AMR) emergence within patients and how these vary across bacterial infections are poorly understood. Increasingly widespread use of pathogen genome sequencing in the clinic enables a deeper understanding of these processes. In this Review, we explore the clinical evidence to support four major mechanisms of within-patient AMR emergence in bacteria: spontaneous resistance mutations; in situ horizontal gene transfer of resistance genes; selection of pre-existing resistance; and immigration of resistant lineages. Within-patient AMR emergence occurs across a wide range of host niches and bacterial species, but the importance of each mechanism varies between bacterial species and infection sites within the body. We identify potential drivers of such differences and discuss how ecological and evolutionary analysis could be embedded within clinical trials of antimicrobials, which are powerful but underused tools for understanding why these mechanisms vary between pathogens, infections and individuals. Ultimately, improving understanding of how host niche, bacterial species and antibiotic mode of action combine to govern the ecological and evolutionary mechanism of AMR emergence in patients will enable more predictive and personalized diagnosis and antimicrobial therapies. | 2024 | 38689039 |
| 9472 | 17 | 0.9996 | Bacteriophage and Bacterial Susceptibility, Resistance, and Tolerance to Antibiotics. Bacteriophages, viruses that infect and replicate within bacteria, impact bacterial responses to antibiotics in complex ways. Recent studies using lytic bacteriophages to treat bacterial infections (phage therapy) demonstrate that phages can promote susceptibility to chemical antibiotics and that phage/antibiotic synergy is possible. However, both lytic and lysogenic bacteriophages can contribute to antimicrobial resistance. In particular, some phages mediate the horizontal transfer of antibiotic resistance genes between bacteria via transduction and other mechanisms. In addition, chronic infection filamentous phages can promote antimicrobial tolerance, the ability of bacteria to persist in the face of antibiotics. In particular, filamentous phages serve as structural elements in bacterial biofilms and prevent the penetration of antibiotics. Over time, these contributions to antibiotic tolerance favor the selection of resistance clones. Here, we review recent insights into bacteriophage contributions to antibiotic susceptibility, resistance, and tolerance. We discuss the mechanisms involved in these effects and address their impact on bacterial fitness. | 2022 | 35890320 |
| 4244 | 18 | 0.9996 | Molecular mechanisms of antibiotic resistance. Antibiotic-resistant bacteria that are difficult or impossible to treat are becoming increasingly common and are causing a global health crisis. Antibiotic resistance is encoded by several genes, many of which can transfer between bacteria. New resistance mechanisms are constantly being described, and new genes and vectors of transmission are identified on a regular basis. This article reviews recent advances in our understanding of the mechanisms by which bacteria are either intrinsically resistant or acquire resistance to antibiotics, including the prevention of access to drug targets, changes in the structure and protection of antibiotic targets and the direct modification or inactivation of antibiotics. | 2015 | 25435309 |
| 9565 | 19 | 0.9996 | Finding drug targets in microbial genomes. In this era of genomic science, knowledge about biological function is integrated increasingly with DNA sequence data. One area that has been significantly impacted by this accumulation of information is the discovery of drugs to treat microbial infections. Genome sequencing and bioinformatics is driving the discovery and development of novel classes of broad-spectrum antimicrobial compounds, and could enable medical science to keep pace with the increasing resistance of bacteria, fungi and parasites to current antimicrobials. This review discusses the use of genomic information in the rapid identification of target genes for antimicrobial drug discovery. | 2001 | 11522517 |