# | Rank | Similarity | Title + Abs. | Year | PMID |
|---|---|---|---|---|---|
| 0 | 1 | 2 | 3 | 4 | 5 |
| 9171 | 0 | 0.9989 | Small molecules modulating AHL-based quorum sensing to attenuate bacteria virulence and biofilms as promising antimicrobial drugs. Clinically significant antibiotic resistance is one of the greatest challenges of the twenty-first century. Yet new antibiotics are currently being developed at a much slower pace than our growing need for such drugs. Instead of focusing on conventional therapeutics that target in vitro bacterial viability, an alternative therapy is to target virulence factors and biofilms. Such anti-virulence strategies have attracted more and more attention recently, for it would add both supplement and diversity to our current antimicrobial library. This approach has several potential advantages including imposing less evolutionary pressure on the development of antibiotic resistance, increasing the antibacterial targets and preserving the host endogenous microbiome. Quorum sensing is an intercellular communication process in bacterial communities, which can regulate coordinated expression of virulence factors and biofilms. N-Acyl homoserine lactones (AHLs) are autoinducers generated by a variety of Gram-negative bacteria. These signals combining with their cognate LuxR-type receptors trigger the expression of virulence genes. In this critical review, we summarize various structural types of small molecules targeting AHL-based quorum sensing to attenuate bacteria virulence factors and biofilms. | 2014 | 24164200 |
| 9585 | 1 | 0.9988 | When Humans Met Superbugs: Strategies to Tackle Bacterial Resistances to Antibiotics. Bacterial resistance to antibiotics poses enormous health and economic burdens to our society, and it is of the essence to explore old and new ways to deal with these problems. Here we review the current status of multi-resistance genes and how they spread among bacteria. We discuss strategies to deal with resistant bacteria, namely the search for new targets and the use of inhibitors of protein-protein interactions, fragment-based methods, or modified antisense RNAs. Finally, we discuss integrated approaches that consider bacterial populations and their niches, as well as the role of global regulators that activate and/or repress the expression of multiple genes in fluctuating environments and, therefore, enable resistant bacteria to colonize new niches. Understanding how the global regulatory circuits work is, probably, the best way to tackle bacterial resistance. | 2018 | 30811343 |
| 9136 | 2 | 0.9988 | Histidine kinase-mediated signal transduction systems of pathogenic microorganisms as targets for therapeutic intervention. Pathogenic bacteria must be able to sense and respond rapidly to signals emanating from the host environment and use the signals to modulate the expression of genes required for the infection process. Two-component signal transduction systems, and their more complex variants known as phosphorelays, are woven within the fabric of bacterial cellular regulatory processes and are used to regulate the expression of genes involved in the virulence and antibiotic resistance responses of a large number of pathogens of major public health concern. The emergence of strains of pathogenic bacteria that are resistant to multiple antibiotics has driven the search for new targets and/or modes of action for anti-microbial agents. The presence of essential two-component systems in bacteria and the central role that these regulatory systems play in virulence and antibiotic resistance has meant that two-component systems and phosphorelays have been recognized as targets for antimicrobial intervention. This review will discuss the role of these signal transduction pathways in virulence responses and antibiotic sensitivity of pathogenic microorganisms and their potential use as targets for antimicrobial therapy. In addition, the current status on the development of inhibitors specific for two-component systems will be discussed. | 2002 | 12462127 |
| 8337 | 3 | 0.9988 | Dynamic Boolean modelling reveals the influence of energy supply on bacterial efflux pump expression. Antimicrobial resistance (AMR) is a global health issue. One key factor contributing to AMR is the ability of bacteria to export drugs through efflux pumps, which relies on the ATP-dependent expression and interaction of several controlling genes. Recent studies have shown that significant cell-to-cell ATP variability exists within clonal bacterial populations, but the contribution of intrinsic cell-to-cell ATP heterogeneity is generally overlooked in understanding efflux pumps. Here, we consider how ATP variability influences gene regulatory networks controlling expression of efflux pump genes in two bacterial species. We develop and apply a generalizable Boolean modelling framework, developed to incorporate the dependence of gene expression dynamics on available cellular energy supply. Theoretical results show that differences in energy availability can cause pronounced downstream heterogeneity in efflux gene expression. Cells with higher energy availability have a superior response to stressors. Furthermore, in the absence of stress, model bacteria develop heterogeneous pulses of efflux pump gene expression which contribute to a sustained sub-population of cells with increased efflux expression activity, potentially conferring a continuous pool of intrinsically resistant bacteria. This modelling approach thus reveals an important source of heterogeneity in cell responses to antimicrobials and sheds light on potentially targetable aspects of efflux pump-related antimicrobial resistance. | 2022 | 35078338 |
| 9599 | 4 | 0.9988 | Antibiotic export: transporters involved in the final step of natural product production. In the fight against antimicrobial resistance (AMR), antibiotic biosynthetic gene clusters are constantly being discovered. These clusters often include genes for membrane transporters that are involved in the export of the produced natural product during biosynthesis and/or subsequent resistance through active efflux. Despite transporter genes being integral parts of these clusters, study of the function of antibiotic export in natural producers such as Streptomyces spp. remains underexplored, in many cases lagging far behind our understanding of the biosynthetic enzymes. More efficient release of antibiotics by producing cells has potential benefits to industrial biotechnology and understanding the relationships between exporters in natural producers and resistance-associated efflux pumps in pathogens can inform our efforts to understand how AMR spreads. Herein we compile and critically assess the literature on the identification and characterization of antibiotic exporters and their contribution to production in natural antibiotic producers. We evaluate examples of how this knowledge could be used in biotechnology to increase yields of the final product or modulate its chemical nature. Finally, we consider the evidence that natural exporters form a reservoir of protein functions that could be hijacked by pathogens as efflux pumps and emphasize the need for much greater understanding of these exporters to fully exploit their potential for applications around human health. | 2019 | 30964430 |
| 9148 | 5 | 0.9988 | Biofilms as Battlefield Armor for Bacteria against Antibiotics: Challenges and Combating Strategies. Bacterial biofilms are formed by communities, which are encased in a matrix of extracellular polymeric substances (EPS). Notably, bacteria in biofilms display a set of 'emergent properties' that vary considerably from free-living bacterial cells. Biofilms help bacteria to survive under multiple stressful conditions such as providing immunity against antibiotics. Apart from the provision of multi-layered defense for enabling poor antibiotic absorption and adaptive persistor cells, biofilms utilize their extracellular components, e.g., extracellular DNA (eDNA), chemical-like catalase, various genes and their regulators to combat antibiotics. The response of biofilms depends on the type of antibiotic that comes into contact with biofilms. For example, excessive production of eDNA exerts resistance against cell wall and DNA targeting antibiotics and the release of antagonist chemicals neutralizes cell membrane inhibitors, whereas the induction of protein and folic acid antibiotics inside cells is lowered by mutating genes and their regulators. Here, we review the current state of knowledge of biofilm-based resistance to various antibiotic classes in bacteria and genes responsible for biofilm development, and the key role of quorum sensing in developing biofilms and antibiotic resistance is also discussed. In this review, we also highlight new and modified techniques such as CRISPR/Cas, nanotechnology and bacteriophage therapy. These technologies might be useful to eliminate pathogens residing in biofilms by combating biofilm-induced antibiotic resistance and making this world free of antibiotic resistance. | 2023 | 37894253 |
| 9150 | 6 | 0.9988 | Microbial silver resistance mechanisms: recent developments. In this mini-review, after a brief introduction into the widespread antimicrobial use of silver ions and nanoparticles against bacteria, fungi and viruses, the toxicity of silver compounds and the molecular mechanisms of microbial silver resistance are discussed, including recent studies on bacteria and fungi. The similarities and differences between silver ions and silver nanoparticles as antimicrobial agents are also mentioned. Regarding bacterial ionic silver resistance, the roles of the sil operon, silver cation efflux proteins, and copper-silver efflux systems are explained. The importance of bacterially produced exopolysaccharides as a physiological (biofilm) defense mechanism against silver nanoparticles is also emphasized. Regarding fungal silver resistance, the roles of metallothioneins, copper-transporting P-type ATPases and cell wall are discussed. Recent evolutionary engineering (adaptive laboratory evolution) studies are also discussed which revealed that silver resistance can evolve rapidly in bacteria and fungi. The cross-resistance observed between silver resistance and resistance to other heavy metals and antibiotics in bacteria and fungi is also explained as a clinically and environmentally important issue. The use of silver against bacterial and fungal biofilm formation is also discussed. Finally, the antiviral effects of silver and the use of silver nanoparticles against SARS-CoV-2 and other viruses are mentioned. To conclude, silver compounds are becoming increasingly important as antimicrobial agents, and their widespread use necessitates detailed understanding of microbial silver response and resistance mechanisms, as well as the ecological effects of silver compounds. Figure created with BioRender.com. | 2022 | 35821348 |
| 9595 | 7 | 0.9988 | Targeted antibiotic discovery through biosynthesis-associated resistance determinants: target directed genome mining. Intense competition between microbes in the environment has directed the evolution of antibiotic production in bacteria. Humans have harnessed these natural molecules for medicinal purposes, magnifying them from environmental concentrations to industrial scale. This increased exposure to antibiotics has amplified antibiotic resistance across bacteria, spurring a global antimicrobial crisis and a search for antibiotics with new modes of action. Genetic insights into these antibiotic-producing microbes reveal that they have evolved several resistance strategies to avoid self-toxicity, including product modification, substrate transport and binding, and target duplication or modification. Of these mechanisms, target duplication or modification will be highlighted in this review, as it uniquely links an antibiotic to its mode of action. We will further discuss and propose a strategy to mine microbial genomes for these genes and their associated biosynthetic gene clusters to discover novel antibiotics using target directed genome mining. | 2019 | 30985219 |
| 8341 | 8 | 0.9988 | Mutagenesis and Resistance Development of Bacteria Challenged by Silver Nanoparticles. Because of their extremely broad spectrum and strong biocidal power, nanoparticles of metals, especially silver (AgNPs), have been widely applied as effective antimicrobial agents against bacteria, fungi, and so on. However, the mutagenic effects of AgNPs and resistance mechanisms of target cells remain controversial. In this study, we discover that AgNPs do not speed up resistance mutation generation by accelerating genome-wide mutation rate of the target bacterium Escherichia coli. AgNPs-treated bacteria also show decreased expression in quorum sensing (QS), one of the major mechanisms leading to population-level drug resistance in microbes. Nonetheless, these nanomaterials are not immune to resistance development by bacteria. Gene expression analysis, experimental evolution in response to sublethal or bactericidal AgNPs treatments, and gene editing reveal that bacteria acquire resistance mainly through two-component regulatory systems, especially those involved in metal detoxification, osmoregulation, and energy metabolism. Although these findings imply low mutagenic risks of nanomaterial-based antimicrobial agents, they also highlight the capacity for bacteria to evolve resistance. | 2022 | 36094196 |
| 9596 | 9 | 0.9988 | Revealing AMP mechanisms of action through resistance evolution and quantitative proteomics. Antimicrobial resistance (AMR) is a significant public health issue that threatens our ability to treat common infections. AMR often emerges in bacteria through upregulation of proteins that allow a subpopulation of resistant bacteria to proliferate through natural selection. Identifying these proteins is crucial for understanding how AMR develops in bacteria and is essential in developing novel therapeutics to combat the threat of widespread AMR. Mass spectrometry-based proteomics is a powerful tool for understanding the biochemical pathways of biological systems, lending remarkable insight into AMR mechanisms in bacteria through measuring the changing protein abundances as a result of antibiotic treatment. Here, we describe a serial passaging method for evolving resistance in bacteria that implements quantitative proteomics to reveal the differential proteomes of resistant bacteria. The focus herein is on antimicrobial peptides (AMPs), but the approach can be generalized for any antimicrobial compound. Comparative proteomics of sensitive vs. resistance strains in response to AMP treatment reveals mechanisms to survive the bioactive compound and points to the mechanism of action for novel AMPs. | 2022 | 35168792 |
| 8278 | 10 | 0.9988 | Siderophore cheating and cheating resistance shape competition for iron in soil and freshwater Pseudomonas communities. All social organisms experience dilemmas between cooperators performing group-beneficial actions and cheats selfishly exploiting these actions. Although bacteria have become model organisms to study social dilemmas in laboratory systems, we know little about their relevance in natural communities. Here, we show that social interactions mediated by a single shareable compound necessary for growth (the iron-scavenging pyoverdine) have important consequences for competitive dynamics in soil and pond communities of Pseudomonas bacteria. We find that pyoverdine non- and low-producers co-occur in many natural communities. While non-producers have genes coding for multiple pyoverdine receptors and are able to exploit compatible heterologous pyoverdines from other community members, producers differ in the pyoverdine types they secrete, offering protection against exploitation from non-producers with incompatible receptors. Our findings indicate that there is both selection for cheating and cheating resistance, which could drive antagonistic co-evolution and diversification in natural bacterial communities.Lab strains of Pseudomonas are model systems for the evolution of cooperation over public goods (iron-scavenging siderophores). Here, Butaitė et al. add ecological and evolutionary insight into this system by showing that cheating and resistance to cheating both shape competition for iron in natural Pseudomonas communities. | 2017 | 28871205 |
| 9608 | 11 | 0.9988 | 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 |
| 9128 | 12 | 0.9988 | Molecular Mechanisms of Bacterial Resistance to Antimicrobial Peptides in the Modern Era: An Updated Review. Antimicrobial resistance (AMR) poses a serious global health concern, resulting in a significant number of deaths annually due to infections that are resistant to treatment. Amidst this crisis, antimicrobial peptides (AMPs) have emerged as promising alternatives to conventional antibiotics (ATBs). These cationic peptides, naturally produced by all kingdoms of life, play a crucial role in the innate immune system of multicellular organisms and in bacterial interspecies competition by exhibiting broad-spectrum activity against bacteria, fungi, viruses, and parasites. AMPs target bacterial pathogens through multiple mechanisms, most importantly by disrupting their membranes, leading to cell lysis. However, bacterial resistance to host AMPs has emerged due to a slow co-evolutionary process between microorganisms and their hosts. Alarmingly, the development of resistance to last-resort AMPs in the treatment of MDR infections, such as colistin, is attributed to the misuse of this peptide and the high rate of horizontal genetic transfer of the corresponding resistance genes. AMP-resistant bacteria employ diverse mechanisms, including but not limited to proteolytic degradation, extracellular trapping and inactivation, active efflux, as well as complex modifications in bacterial cell wall and membrane structures. This review comprehensively examines all constitutive and inducible molecular resistance mechanisms to AMPs supported by experimental evidence described to date in bacterial pathogens. We also explore the specificity of these mechanisms toward structurally diverse AMPs to broaden and enhance their potential in developing and applying them as therapeutics for MDR bacteria. Additionally, we provide insights into the significance of AMP resistance within the context of host-pathogen interactions. | 2024 | 39065030 |
| 9543 | 13 | 0.9988 | Antisense RNA regulation and application in the development of novel antibiotics to combat multidrug resistant bacteria. Despite the availability of antibiotics and vaccines, infectious diseases remain one of most dangerous threats to humans and animals. The overuse and misuse of antibacterial agents have led to the emergence of multidrug resistant bacterial pathogens. Bacterial cells are often resilient enough to survive in even the most extreme environments. To do so, the organisms have evolved different mechanisms, including a variety of two-component signal transduction systems, which allow the bacteria to sense the surrounding environment and regulate gene expression in order to adapt and respond to environmental stimuli. In addition, some bacteria evolve resistance to antibacterial agents while many bacterial cells are able to acquire resistance genes from other bacterial species to enable them to survive in the presence of toxic antimicrobial agents. The crisis of antimicrobial resistance is an unremitting menace to human health and a burden on public health. The rapid increase in antimicrobial resistant organisms and limited options for development of new classes of antibiotics heighten the urgent need to develop novel potent antibacterial therapeutics in order to combat multidrug resistant infections. In this review, we introduce the regulatory mechanisms of antisense RNA and significant applications of regulated antisense RNA interference technology in early drug discovery. This includes the identification and evaluation of drug targets in vitro and in vivo, the determination of mode of action for antibiotics and new antibacterial agents, as well as the development of peptide-nucleic acid conjugates as novel antibacterials. | 2013 | 23738437 |
| 9423 | 14 | 0.9988 | Integrated evolutionary analysis reveals antimicrobial peptides with limited resistance. Antimicrobial peptides (AMPs) are promising antimicrobials, however, the potential of bacterial resistance is a major concern. Here we systematically study the evolution of resistance to 14 chemically diverse AMPs and 12 antibiotics in Escherichia coli. Our work indicates that evolution of resistance against certain AMPs, such as tachyplesin II and cecropin P1, is limited. Resistance level provided by point mutations and gene amplification is very low and antibiotic-resistant bacteria display no cross-resistance to these AMPs. Moreover, genomic fragments derived from a wide range of soil bacteria confer no detectable resistance against these AMPs when introduced into native host bacteria on plasmids. We have found that simple physicochemical features dictate bacterial propensity to evolve resistance against AMPs. Our work could serve as a promising source for the development of new AMP-based therapeutics less prone to resistance, a feature necessary to avoid any possible interference with our innate immune system. | 2019 | 31586049 |
| 9598 | 15 | 0.9988 | Strategies and molecular tools to fight antimicrobial resistance: resistome, transcriptome, and antimicrobial peptides. The increasing number of antibiotic resistant bacteria motivates prospective research toward discovery of new antimicrobial active substances. There are, however, controversies concerning the cost-effectiveness of such research with regards to the description of new substances with novel cellular interactions, or description of new uses of existing substances to overcome resistance. Although examination of bacteria isolated from remote locations with limited exposure to humans has revealed an absence of antibiotic resistance genes, it is accepted that these genes were both abundant and diverse in ancient living organisms, as detected in DNA recovered from Pleistocene deposits (30,000 years ago). Indeed, even before the first clinical use of antibiotics more than 60 years ago, resistant organisms had been isolated. Bacteria can exhibit different strategies for resistance against antibiotics. New genetic information may lead to the modification of protein structure affecting the antibiotic carriage into the cell, enzymatic inactivation of drugs, or even modification of cellular structure interfering in the drug-bacteria interaction. There are still plenty of new genes out there in the environment that can be appropriated by putative pathogenic bacteria to resist antimicrobial agents. On the other hand, there are several natural compounds with antibiotic activity that may be used to oppose them. Antimicrobial peptides (AMPs) are molecules which are wide-spread in all forms of life, from multi-cellular organisms to bacterial cells used to interfere with microbial growth. Several AMPs have been shown to be effective against multi-drug resistant bacteria and have low propensity to resistance development, probably due to their unique mode of action, different from well-known antimicrobial drugs. These substances may interact in different ways with bacterial cell membrane, protein synthesis, protein modulation, and protein folding. The analysis of bacterial transcriptome may contribute to the understanding of microbial strategies under different environmental stresses and allows the understanding of their interaction with novel AMPs. | 2013 | 24427156 |
| 9594 | 16 | 0.9988 | Electroactive Smart Materials: Novel Tools for Tailoring Bacteria Behavior and Fight Antimicrobial Resistance. Despite being very simple organisms, bacteria possess an outstanding ability to adapt to different environments. Their long evolutionary history, being exposed to vastly different physicochemical surroundings, allowed them to detect and respond to a wide range of signals including biochemical, mechanical, electrical, and magnetic ones. Taking into consideration their adapting mechanisms, it is expected that novel materials able to provide bacteria with specific stimuli in a biomimetic context may tailor their behavior and make them suitable for specific applications in terms of anti-microbial and pro-microbial approaches. This review maintains that electroactive smart materials will be a future approach to be explored in microbiology to obtain novel strategies for fighting the emergence of live threatening antibiotic resistance. | 2019 | 31681752 |
| 9137 | 17 | 0.9988 | Virulence- and antibiotic resistance-associated two-component signal transduction systems of Gram-positive pathogenic bacteria as targets for antimicrobial therapy. Two-component signal transduction systems are central elements of the virulence and antibiotic resistance responses of opportunistic bacterial pathogens. These systems allow the bacterium to sense and respond to signals emanating from the host environment and to modulate the repertoire of genes expressed to allow invasion and growth in the host. The integral role of two-component systems in virulence and antibiotic sensitivity, and the existence of essential two-component systems in several pathogenic bacteria, suggests that these systems may be novel targets for antimicrobial intervention. This review discusses the potential use of two-component systems as targets for antimicrobial therapy against Gram-positive pathogens and the current status in the development of inhibitors specific for these systems. | 2002 | 12191621 |
| 9152 | 18 | 0.9988 | Pseudomonas aeruginosa biofilm sensitivity to biocides: use of hydrogen peroxide as model antimicrobial agent for examining resistance mechanisms. The biofilm mode of bacterial growth may be the preferred form of existence in nature. Because of the global impact of problematic biofilms, study of the mechanisms affording resistance to various biocides is of dire importance. Furthermore, understanding the physiological differences between biofilm and planktonic organisms ranks particularly high on the list of important and necessary research. Such contributions will only serve to broaden our knowledge base, especially regarding the development of better antimicrobials while also fine-tuning the use of current highly effective antimicrobials. Using H2O2 as a model oxidizing biocide, we demonstrate the marked resistance of biofilm bacteria relative to planktonic cells. Because many biocides are good oxidizing agents (e.g., H2O2, HOCl), understanding the mechanisms by which genes involved in combating oxidative stress are activated is important in determining the overall efficacy of such biocides. Future studies will focus on determining mechanisms of oxidative stress gene regulation in bacterial biofilms. | 1999 | 10547822 |
| 9597 | 19 | 0.9988 | 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 |