Antibacterial particles and predatory bacteria as alternatives to antibacterial chemicals in the era of antibiotic resistance. - Related Documents




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958701.0000Antibacterial particles and predatory bacteria as alternatives to antibacterial chemicals in the era of antibiotic resistance. This review is focused on the subset of antibacterial agents whose action involves one-on-one targeting of infecting bacteria. These agents target individual bacteria and their efficacy is based on particle numbers in contrast to chemical agents such as antibiotics, whose efficacy is based on minimal inhibitory concentrations. Four extant members of this class are predatory bacteria, functional (plaque-forming) phages, and engineered particulate systems, phagemids (plasmids that contain a phage packaging signal) and antibacterial drones (ABDs) that package chromosomal island DNA carrying antibacterial genes. We differentiate the natural predators, phages and predatory bacteria, from the engineered delivery vehicles, phagemids and ABDs, because the latter are much more versatile and can largely bypass the historical warfare that informs the predator-prey interactions.202134688038
913010.9998Glycopeptide antibiotic resistance. Glycopeptide antibiotics are integral components of the current antibiotic arsenal that is under strong pressures as a result of the emergence of a variety of resistance mechanisms over the past 15 years. Resistance has manifested itself largely through the expression of genes that encode proteins that reprogram cell wall biosynthesis and thus evade the action of the antibiotic in the enterococci, though recently new mechanisms have appeared that afford resistance and tolerance in the more virulent staphylococci and streptococci. Overcoming glycopeptide resistance will require innovative approaches to generate new antibiotics or otherwise to inhibit the action of resistance elements in various bacteria. The chemical complexity of the glycopeptides, the challenges of discovering and successfully exploiting new targets, and the growing number of distinct resistance types all increase the difficulty of the current problem we face as a result of the emergence of glycopeptide resistance.200211807177
959020.9998Recent advances in phage defense systems and potential overcoming strategies. Bacteriophages are effective in the prevention and control of bacteria, and many phage products have been permitted and applied in the field. Because bacteriophages are expected to replace other antimicrobial agents like antibiotics, the antibacterial effect of bacteriophage has attracted widespread attention. Recently, the diversified defense systems discovered in the target host have become potential threats to the continued effective application of phages. Therefore, a systematic summary and in-depth illustration of the interaction between phages and bacteria is conducive to the development of this biological control approach. In this review, we introduce different defense systems in bacteria against phages and emphasize newly discovered defense mechanisms in recent years. Additionally, we draw attention to the striking resemblance between defense system genes and antibiotic resistance genes, which raises concerns about the potential transfer of phage defense systems within bacterial populations and its future impact on phage efficacy. Thus, attention should be given to the effects of phage defense genes in practical applications. This article is not exhaustive, but strategies to overcome phage defense systems are also discussed to further promote more efficient use of phages.202337037289
947230.9997Bacteriophage 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.202235890320
914940.9997Smart Multifunctional Polymer Systems as Alternatives or Supplements of Antibiotics To Overcome Bacterial Resistance. In recent years, infectious diseases have again become a critical threat to global public health largely due to the challenges posed by antimicrobial resistance. Conventional antibiotics have played a crucial role in combating bacterial infections; however, their efficacy is significantly impaired by widespread drug resistance. Natural antimicrobial peptides (AMPs) and their polymeric mimics demonstrate great potential for killing bacteria with low propensity of resistance as they target the microbial membrane rather than a specific molecular target, but they are also toxic to the host eukaryotic cells. To minimize antibiotics systemic spread and the required dose that promote resistance and to advocate practical realization of the promising activity of AMPs and polymers, smart systems to target bacteria are highly sought after. This review presents bacterial recognition by various specific targeting molecules and the delivery systems of active components in supramolecules. Bacteria-induced activations of antimicrobial-based nanoformulations are also included. Recent advances in the bacteria targeting and delivery of synthetic antimicrobial agents may assist in developing new classes of highly selective antimicrobial systems which can improve bactericidal efficacy and greatly minimize the spread of bacterial resistance.202235471022
959150.9997Interaction of phages, bacteria, and the human immune system: Evolutionary changes in phage therapy. Phages and bacteria are known to undergo dynamic and co-evolutionary arms race interactions in order to survive. Recent advances from in vitro and in vivo studies have improved our understanding of the complex interactions between phages, bacteria, and the human immune system. This insight is essential for the development of phage therapy to battle the growing problems of antibiotic resistance. It is also pivotal to prevent the development of phage-resistance during the implementation of phage therapy in the clinic. In this review, we discuss recent progress of the interactions between phages, bacteria, and the human immune system and its clinical application for phage therapy. Proper phage therapy design will ideally produce large burst sizes, short latent periods, broad host ranges, and a low tendency to select resistance.201931145517
917660.9997Evolutionary Dynamics between Phages and Bacteria as a Possible Approach for Designing Effective Phage Therapies against Antibiotic-Resistant Bacteria. With the increasing global threat of antibiotic resistance, there is an urgent need to develop new effective therapies to tackle antibiotic-resistant bacterial infections. Bacteriophage therapy is considered as a possible alternative over antibiotics to treat antibiotic-resistant bacteria. However, bacteria can evolve resistance towards bacteriophages through antiphage defense mechanisms, which is a major limitation of phage therapy. The antiphage mechanisms target the phage life cycle, including adsorption, the injection of DNA, synthesis, the assembly of phage particles, and the release of progeny virions. The non-specific bacterial defense mechanisms include adsorption inhibition, superinfection exclusion, restriction-modification, and abortive infection systems. The antiphage defense mechanism includes a clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated (Cas) system. At the same time, phages can execute a counterstrategy against antiphage defense mechanisms. However, the antibiotic susceptibility and antibiotic resistance in bacteriophage-resistant bacteria still remain unclear in terms of evolutionary trade-offs and trade-ups between phages and bacteria. Since phage resistance has been a major barrier in phage therapy, the trade-offs can be a possible approach to design effective bacteriophage-mediated intervention strategies. Specifically, the trade-offs between phage resistance and antibiotic resistance can be used as therapeutic models for promoting antibiotic susceptibility and reducing virulence traits, known as bacteriophage steering or evolutionary medicine. Therefore, this review highlights the synergistic application of bacteriophages and antibiotics in association with the pleiotropic trade-offs of bacteriophage resistance.202235884169
829070.9997Antimicrobial Peptides: Features, Action, and Their Resistance Mechanisms in Bacteria. In recent years, because of increased resistance to conventional antimicrobials, many researchers have started to study the synthesis of new antibiotics to control the disease-causing effects of infectious pathogens. Antimicrobial peptides (AMPs) are among the newest antibiotics; these peptides are integral compounds in all kinds of organisms and play a significant role in microbial ecology, and critically contribute to the innate immunity of organisms by destroying invading microorganisms. Moreover, AMPs may encourage cells to produce chemokines, stimulate angiogenesis, accelerate wound healing, and influence programmed cell death in multicellular organisms. Bacteria differ in their inherent susceptibility and resistance mechanisms to these peptides when responding to the antimicrobial effects of AMPs. Generally, the development of AMP resistance mechanisms is driven by direct competition between bacterial species, and host and pathogen interactions. Several studies have shown diverse mechanisms of bacterial resistance to AMPs, for example, some bacteria produce proteases and trapping proteins; some modify cell surface charge, change membrane fluidity, and activate efflux pumps; and some species make use of biofilms and exopolymers, and develop sensing systems by selective gene expression. A closer understanding of bacterial resistance mechanisms may help in developing novel therapeutic approaches for the treatment of infections caused by pathogenic organisms that are successful in developing extensive resistance to AMPs. Based on these observations, this review discusses the properties of AMPs, their targeting mechanisms, and bacterial resistance mechanisms against AMPs.201829957118
959880.9997Strategies 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.201324427156
912890.9997Molecular 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.202439065030
8266100.9997Remarkable Mechanisms in Microbes to Resist Phage Infections. Bacteriophages (phages) specifically infect bacteria and are the most abundant biological entities on Earth. The constant exposure to phage infection imposes a strong selective pressure on bacteria to develop viral resistance strategies that promote prokaryotic survival. Thus, this parasite-host relationship results in an evolutionary arms race of adaptation and counteradaptation between the interacting partners. The evolutionary outcome is a spectrum of remarkable strategies used by the bacteria and phages as they attempt to coexist. These approaches include adsorption inhibition, injection blocking, abortive infection, toxin-antitoxin, and CRISPR-Cas systems. In this review, we highlight the diverse and complementary antiphage systems in bacteria, as well as the evasion mechanisms used by phages to escape these resistance strategies.201426958724
9131110.9997How do antibiotic-producing bacteria ensure their self-resistance before antibiotic biosynthesis incapacitates them? Acquired antibiotic resistance among dangerous bacterial pathogens is an increasing medical problem. While in Mycobacterium tuberculosis this occurs by mutation in the genes encoding the targets for antibiotic action, other pathogens have generally gained their resistance genes by horizontal gene transfer from non-pathogenic bacteria. The ultimate source of many of these genes is almost certainly the actinomycetes that make the antibiotics and therefore need self-protective mechanisms to avoid suicide. How do they ensure that they are resistant at the time when intracellular antibiotic concentrations reach potentially lethal levels? In this issue of Molecular Microbiology, Tahlan et al. describe a solution to this problem in which an antibiotically inactive precursor of a Streptomyces coelicolor antibiotic induces resistance -- in this example by means of a trans-membrane export pump -- so that the organism is already primed for resistance at the time when it is needed. The authors generalize their interpretation to other cases where antibiotic resistance depends on export, but it will be interesting to find out whether it could in fact apply more widely, to include the other major mechanisms of resistance: target modification and the synthesis of antibiotics via a series of chemically modified intermediates, with removal of the protective group at the time of secretion into the outside medium.200717238916
9206120.9997Susceptibility reversed: modified plant susceptibility genes for resistance to bacteria. Plants have evolved complex defence mechanisms to avoid invasion of potential pathogens. Despite this, adapted pathogens deploy effector proteins to manipulate host susceptibility (S) genes, rendering plant defences ineffective. The identification and mutation of plant S genes exploited by bacterial pathogens are important for the generation of crops with durable and broad-spectrum resistance. Application of mutant S genes in the breeding of resistant crops is limited because of potential pleiotropy. New genome editing techniques open up new possibilities for the modification of S genes. In this review, we focus on S genes manipulated by bacteria and propose ways for their identification and precise modification. Finally, we propose that genes coding for transporter proteins represent a new group of S genes.202234400073
9541130.9997The Role of the Hfq Protein in Bacterial Resistance to Antibiotics: A Narrative Review. The antibiotic resistance of pathogenic microorganisms is currently one of most major medical problems, causing a few million deaths every year worldwide due to untreatable bacterial infections. Unfortunately, the prognosis is even worse, as over 8 million deaths associated with antibiotic resistance are expected to occur in 2050 if no new effective antibacterial treatments are discovered. The Hfq protein has been discovered as a bacterial RNA chaperone. However, subsequent studies have indicated that this small protein (composed of 102 amino acid residues in Escherichia coli) has more activities, including binding to DNA and influencing its compaction, interaction with biological membranes, formation of amyloid-like structures, and others. Although Hfq is known to participate in many cellular processes, perhaps surprisingly, only reports from recent years have demonstrated its role in bacterial antibiotic resistance. The aim of this narrative review is to discuss how can Hfq affects antibiotic resistance in bacteria and propose how this knowledge may facilitate developing new therapeutic strategies against pathogenic bacteria. We indicate that the mechanisms by which the Hfq protein modulates the response of bacterial cells to antibiotics are quite different, from the regulation of the expression of genes coding for proteins directly involved in antibiotic transportation or action, through direct effects on membranes, to controlling the replication or transposition of mobile genetic elements bearing antibiotic resistance genes. Therefore, we suggest that Hfq could be considered a potential target for novel antimicrobial compounds. We also discuss difficulties in developing such drugs, but since Hfq appears to be a promising target for drugs that may enhance the efficacy of antibiotics, we propose that works on such potential therapeutics are encouraged.202540005731
9543140.9997Antisense 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.201323738437
9132150.9997Antibiotic resistance: a survival strategy. Antibiotics are natural, semi-synthetic, or synthetic molecules that target the cell wall of bacteria, DNA replication, RNA transcription, or mRNA translation, the cellular machinery responsible for the synthesis of precursor molecules. Bacteria have evolved and adopted numerous strategies to counteract the action of antibiotics. Antibiotic resistance is intrinsic and an inherent characteristic of the microorganism. Intrinsic resistance is due to cell wall impermeability, efflux, biofilm formation, and the expression of genes mediating inactivating enzymes. Antibiotic resistance can also arise by the acquisition of extracellular DNA and is expressed phenotypically as efflux, modification or acquisition of target sites, and enzymatic inactivation of the antibiotic. Not only have bacteria acquired the mechanisms necessary to withstand the effects of antibiotics, they have also acquired elaborate mechanisms to mobilize and disseminate these successful strategies: plasmids, transposons, insertion sequences, and cassettes. Antibiotic resistance is a major worldwide clinical problem of public health concern because of the reduced efficacy caused by the various mechanisms of resistance. Global strategies are emerging to help address this critical problem.200516134477
9469160.9997Reversing bacterial resistance to antibiotics by phage-mediated delivery of dominant sensitive genes. Pathogen resistance to antibiotics is a rapidly growing problem, leading to an urgent need for novel antimicrobial agents. Unfortunately, development of new antibiotics faces numerous obstacles, and a method that resensitizes pathogens to approved antibiotics therefore holds key advantages. We present a proof of principle for a system that restores antibiotic efficiency by reversing pathogen resistance. This system uses temperate phages to introduce, by lysogenization, the genes rpsL and gyrA conferring sensitivity in a dominant fashion to two antibiotics, streptomycin and nalidixic acid, respectively. Unique selective pressure is generated to enrich for bacteria that harbor the phages carrying the sensitizing constructs. This selection pressure is based on a toxic compound, tellurite, and therefore does not forfeit any antibiotic for the sensitization procedure. We further demonstrate a possible way of reducing undesirable recombination events by synthesizing dominant sensitive genes with major barriers to homologous recombination. Such synthesis does not significantly reduce the gene's sensitization ability. Unlike conventional bacteriophage therapy, the system does not rely on the phage's ability to kill pathogens in the infected host, but instead, on its ability to deliver genetic constructs into the bacteria and thus render them sensitive to antibiotics prior to host infection. We believe that transfer of the sensitizing cassette by the constructed phage will significantly enrich for antibiotic-treatable pathogens on hospital surfaces. Broad usage of the proposed system, in contrast to antibiotics and phage therapy, will potentially change the nature of nosocomial infections toward being more susceptible to antibiotics rather than more resistant.201222113912
9133170.9997Overcoming antimicrobial resistance by targeting resistance mechanisms. Three mechanisms of antimicrobial resistance predominate in bacteria: antibiotic inactivation, target site modification, and altered uptake by way of restricted entry and/or enhanced efflux. Many of these involve enzymes or transport proteins whose activity can be targeted directly in an attemptto compromise resistance and, thus, potentiate antimicrobial activity. Alternatively, novel agents unaffected by these resistance mechanisms can be developed. Given the ongoing challenge posed by antimicrobial resistance in bacteria, targeting resistance in this way may be our best hope at prolonging the antibiotic era.200111291743
9200180.9997Application of the CRISPR/Cas System for Generation of Pathogen-Resistant Plants. The use of the CRISPR/Cas9 prokaryotic adaptive immune system has led to a breakthrough in targeted genome editing in eukaryotes. The CRISPR/Cas technology allows to generate organisms with desirable characteristics by introducing deletions/insertions into selected genome loci resulting in the knockout or modification of target genes. This review focuses on the current state of the CRISPR/Cas use for the generation of plants resistant to viruses, bacteria, and parasitic fungi. Resistance to DNA- and RNA-containing viruses is usually provided by expression in transgenic plants of the Cas endonuclease gene and short guide RNAs (sgRNAs) targeting certain sites in the viral or the host plant genomes to ensure either direct cleavage of the viral genome or modification of the plant host genome in order to decrease the efficiency of virus replication. Editing of plant genes involved in the defense response to pathogens increases plants resistance to bacteria and pathogenic fungi. The review explores strategies and prospects of the development of pathogen-resistant plants with a focus on the generation of non-transgenic (non-genetically modified) organisms, in particular, by using plasmid (DNA)-free systems for delivery of the Cas/sgRNA editing complex into plant cells.201830878030
9582190.9997Humans and Microbes: A Systems Theory Perspective on Coevolution. The issue of rapid adaptation of microorganisms to changing environments is examined. The mechanism of adaptive mutations is analyzed. The possibility that horizontal gene transfer is a random process is discussed. Bacteria, unicellular fungi, and other microorganisms successfully adapt to fast-changing conditions (such as exposure to drugs) because their evolution is not a random process. Adaptation to antibiotics, adaptive mutations, and related phenomena occur because microbial evolution is inherently directed and purposefully oriented toward potential external changes. Rejecting gene-centricity plays a crucial role in understanding the coevolution of humans and pathogens. This means that beyond genes, there exists a higher-level system-an organism with its own unique properties that cannot be reduced to genes. The problem of human adaptation to infectious agents (viruses, bacteria, and protozoa) is also analyzed. Based on general systems theory, it is concluded that humans and pathogens coevolve in a controlled manner.202541176022