Roles of Regulatory RNAs for Antibiotic Resistance in Bacteria and Their Potential Value as Novel Drug Targets. - Related Documents




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828901.0000Roles of Regulatory RNAs for Antibiotic Resistance in Bacteria and Their Potential Value as Novel Drug Targets. The emergence of antibiotic resistance mechanisms among bacterial pathogens increases the demand for novel treatment strategies. Lately, the contribution of non-coding RNAs to antibiotic resistance and their potential value as drug targets became evident. RNA attenuator elements in mRNA leader regions couple expression of resistance genes to the presence of the cognate antibiotic. Trans-encoded small RNAs (sRNAs) modulate antibiotic tolerance by base-pairing with mRNAs encoding functions important for resistance such as metabolic enzymes, drug efflux pumps, or transport proteins. Bacteria respond with extensive changes of their sRNA repertoire to antibiotics. Each antibiotic generates a unique sRNA profile possibly causing downstream effects that may help to overcome the antibiotic challenge. In consequence, regulatory RNAs including sRNAs and their protein interaction partners such as Hfq may prove useful as targets for antimicrobial chemotherapy. Indeed, several compounds have been developed that kill bacteria by mimicking ligands for riboswitches controlling essential genes, demonstrating that regulatory RNA elements are druggable targets. Drugs acting on sRNAs are considered for combined therapies to treat infections. In this review, we address how regulatory RNAs respond to and establish resistance to antibiotics in bacteria. Approaches to target RNAs involved in intrinsic antibiotic resistance or virulence for chemotherapy will be discussed.201728529506
913310.9998Overcoming 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
828520.9998Bacterial stress response: understanding the molecular mechanics to identify possible therapeutic targets. INTRODUCTION: Bacteria are ubiquitous and many of them are pathogenic in nature. Entry of bacteria in host and its recognition by host defense system induce stress in host cells. With time, bacteria have also developed strategies including drug resistance to escape from antibacterial therapy as well as host defense mechanism. AREAS COVERED: Bacterial stress initiates and promotes adaptive immune response through several integrated mechanisms. The mechanisms of bacteria to up and down regulate different pathways involved in these responses have been discussed. The genetic expression of these pathways can be manipulated by the pharmacological interventions. Present review discusses in these contexts and explores the possibilities to overcome stress induced by bacterial pathogens and to suggest new possible therapeutic targets. EXPERT OPINION: In our opinion, there are two important fronts to regulate the bacterial stress. One is to target caspase involved in the process of transformation and translation at gene level and protein expression. Second is the identification of bacterial genes that lead to synthesis of abnormal end products supporting bacterial survival in host environment and also to surpass the host defense mechanism. Identification of such genes and their expression products could be an effective option to encounter bacterial resistance.202132811215
834330.9998Bacterial Stress Responses as Potential Targets in Overcoming Antibiotic Resistance. Bacteria can be adapted to adverse and detrimental conditions that induce general and specific responses to DNA damage as well as acid, heat, cold, starvation, oxidative, envelope, and osmotic stresses. The stress-triggered regulatory systems are involved in bacterial survival processes, such as adaptation, physiological changes, virulence potential, and antibiotic resistance. Antibiotic susceptibility to several antibiotics is reduced due to the activation of stress responses in cellular physiology by the stimulation of resistance mechanisms, the promotion of a resistant lifestyle (biofilm or persistence), and/or the induction of resistance mutations. Hence, the activation of bacterial stress responses poses a serious threat to the efficacy and clinical success of antibiotic therapy. Bacterial stress responses can be potential targets for therapeutic alternatives to antibiotics. An understanding of the regulation of stress response in association with antibiotic resistance provides useful information for the discovery of novel antimicrobial adjuvants and the development of effective therapeutic strategies to control antibiotic resistance in bacteria. Therefore, this review discusses bacterial stress responses linked to antibiotic resistance in Gram-negative bacteria and also provides information on novel therapies targeting bacterial stress responses that have been identified as potential candidates for the effective control of Gram-negative antibiotic-resistant bacteria.202235889104
829040.9998Antimicrobial 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
916950.9998Interference of bacterial cell-to-cell communication: a new concept of antimicrobial chemotherapy breaks antibiotic resistance. Bacteria use a cell-to-cell communication activity termed "quorum sensing" to coordinate group behaviors in a cell density dependent manner. Quorum sensing influences the expression profile of diverse genes, including antibiotic tolerance and virulence determinants, via specific chemical compounds called "autoinducers". During quorum sensing, Gram-negative bacteria typically use an acylated homoserine lactone (AHL) called autoinducer 1. Since the first discovery of quorum sensing in a marine bacterium, it has been recognized that more than 100 species possess this mechanism of cell-to-cell communication. In addition to being of interest from a biological standpoint, quorum sensing is a potential target for antimicrobial chemotherapy. This unique concept of antimicrobial control relies on reducing the burden of virulence rather than killing the bacteria. It is believed that this approach will not only suppress the development of antibiotic resistance, but will also improve the treatment of refractory infections triggered by multi-drug resistant pathogens. In this paper, we review and track recent progress in studies on AHL inhibitors/modulators from a biological standpoint. It has been discovered that both natural and synthetic compounds can disrupt quorum sensing by a variety of means, such as jamming signal transduction, inhibition of signal production and break-down and trapping of signal compounds. We also focus on the regulatory elements that attenuate quorum sensing activities and discuss their unique properties. Understanding the biological roles of regulatory elements might be useful in developing inhibitor applications and understanding how quorum sensing is controlled.201323720655
828660.9998RNA Modifications in Pathogenic Bacteria: Impact on Host Adaptation and Virulence. RNA modifications are involved in numerous biological processes and are present in all RNA classes. These modifications can be constitutive or modulated in response to adaptive processes. RNA modifications play multiple functions since they can impact RNA base-pairings, recognition by proteins, decoding, as well as RNA structure and stability. However, their roles in stress, environmental adaptation and during infections caused by pathogenic bacteria have just started to be appreciated. With the development of modern technologies in mass spectrometry and deep sequencing, recent examples of modifications regulating host-pathogen interactions have been demonstrated. They show how RNA modifications can regulate immune responses, antibiotic resistance, expression of virulence genes, and bacterial persistence. Here, we illustrate some of these findings, and highlight the strategies used to characterize RNA modifications, and their potential for new therapeutic applications.202134440299
954170.9997The 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
913280.9997Antibiotic 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
916890.9997Novel approaches to bacterial infection therapy by interfering with bacteria-to-bacteria signaling. The growing challenge of antimicrobial resistance and the paucity of novel antibiotics underscore the importance of developing novel therapeutics. Bacterial cell-to-cell signaling constitutes a novel drug target. Quorum sensing (QS) is a cell-to-cell signaling mechanism that refers to the ability of bacteria to respond to chemical hormone-like molecules called autoinducers. QS is responsible for controlling a plethora of virulence genes in several bacterial pathogens. Antagonists to autoinducers will intercept bacterial intercellular communication, hindering their ability to act in a coordinated manner to express virulence traits. Moreover, since QS is not involved directly in essential processes, such as bacterial growth, one can reason that inhibition of QS will not yield a selective pressure for the development of resistance.200717402841
9134100.9997Mechanism of drug resistance in bacteria: efflux pump modulation for designing of new antibiotic enhancers. Drug resistance has now become a serious concern in the domain of microbial infection. Bacteria are becoming smarter by displaying a variety of mechanisms during drug resistance. It is not only helping bacteria to adapt nicely in adverse environment but it also makes a smart system for better availability of nutritional status for microorganisms. In this domain, pathogenic bacteria are extensively studied and their mechanism for drug resistance is well explored. The common modes in bacterial resistance include degradation of antibiotics by enzymes, antibiotic target modification or inactivation by enzymatic actions, complete replacement of antibiotic targets, quorum sensing (QS) mechanism, and efflux pump-based extrusion of antibiotics. In this review, various mechanisms of drug resistance in bacteria have been highlighted with giving the importance of efflux pumps. This can be explored as a knowledge source for the management of a variety of bacterial infections, related disease and vibrant clue for next-generation drug development.202134431062
9125110.9997Coevolution of Resistance Against Antimicrobial Peptides. Antimicrobial peptides (AMPs) are produced by all forms of life, ranging from eukaryotes to prokaryotes, and they are a crucial component of innate immunity, involved in clearing infection by inhibiting pathogen colonization. In the recent past, AMPs received high attention due to the increase of extensive antibiotic resistance by these pathogens. AMPs exhibit a diverse spectrum of activity against bacteria, fungi, parasites, and various types of cancer. AMPs are active against various bacterial pathogens that cause disease in animals and plants. However, because of the coevolution of host and pathogen interaction, bacteria have developed the mechanisms to sense and exhibit an adaptive response against AMPs. These resistance mechanisms are playing an important role in bacterial virulence within the host. Here, we have discussed the different resistance mechanisms used by gram-positive and gram-negative bacteria to sense and combat AMP actions. Understanding the mechanism of AMP resistance may provide directions toward the development of novel therapeutic strategies to control multidrug-resistant pathogens.202032119634
9136120.9997Histidine 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.200212462127
9165130.9997Regulatory Mechanisms and Physiological Impacts of Quorum Sensing in Gram-Negative Bacteria. The Quorum sensing (QS) system is a widely existing communication mechanism, which regulates bacterial community behaviors and the expression of specific genes. The most common pathogenic bacteria in clinical infections are gram-negative bacteria, and QS plays an important regulatory role in the production of virulence factors and development of antibiotic resistance. This article reviews the QS systems of gram-negative bacteria and provides an overview of how they regulate their physiological functions.202439654694
9542140.9997Development of quorum-based anti-virulence therapeutics targeting Gram-negative bacterial pathogens. Quorum sensing is a cell density-dependent signaling phenomenon used by bacteria for coordination of population-wide phenotypes, such as expression of virulence genes, antibiotic resistance and biofilm formation. Lately, disruption of bacterial communication has emerged as an anti-virulence strategy with enormous therapeutic potential given the increasing incidences of drug resistance in pathogenic bacteria. The quorum quenching therapeutic approach promises a lower risk of resistance development, since interference with virulence generally does not affect the growth and fitness of the bacteria and, hence, does not exert an associated selection pressure for drug-resistant strains. With better understanding of bacterial communication networks and mechanisms, many quorum quenching methods have been developed against various clinically significant bacterial pathogens. In particular, Gram-negative bacteria are an important group of pathogens, because, collectively, they are responsible for the majority of hospital-acquired infections. Here, we discuss the current understanding of existing quorum sensing mechanisms and present important inhibitory strategies that have been developed against this group of pathogenic bacteria.201323939429
9171150.9997Small 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.201424164200
9129160.9997Overcoming Intrinsic and Acquired Resistance Mechanisms Associated with the Cell Wall of Gram-Negative Bacteria. The global increase in multi-drug-resistant bacteria is severely impacting our ability to effectively treat common infections. For Gram-negative bacteria, their intrinsic and acquired resistance mechanisms are heightened by their unique cell wall structure. The cell wall, while being a target of some antibiotics, represents a barrier due to the inability of most antibacterial compounds to traverse and reach their intended target. This means that its composition and resulting mechanisms of resistance must be considered when developing new therapies. Here, we discuss potential antibiotic targets within the most well-characterised resistance mechanisms associated with the cell wall in Gram-negative bacteria, including the outer membrane structure, porins and efflux pumps. We also provide a timely update on the current progress of inhibitor development in these areas. Such compounds could represent new avenues for drug discovery as well as adjuvant therapy to help us overcome antibiotic resistance.202032961699
9104170.9997Heterogeneous efflux pump expression underpins phenotypic resistance to antimicrobial peptides. Antimicrobial resistance threatens the viability of modern medical interventions. There is a dire need to develop novel approaches to counter resistance mechanisms employed by starved or slow-growing pathogens that are refractory to conventional antimicrobial therapies. Antimicrobial peptides have been advocated as potential therapeutic solutions due to the low levels of genetic resistance observed in bacteria against these compounds. However, here we show that subpopulations of stationary phase Escherichia coli and Pseudomonas aeruginosa survive tachyplesin treatment without acquiring genetic mutations. These phenotypic variants display enhanced efflux activity to limit intracellular peptide accumulation. Differential regulation of genes involved in outer membrane vesicle secretion, membrane modification, and protease activity was also observed between phenotypically resistant and susceptible cells. We discovered that the formation of these phenotypic variants could be prevented by administering tachyplesin in combination with sertraline, a clinically used antidepressant, suggesting a novel approach for combatting antimicrobial-refractory stationary phase bacteria.202540607907
9167180.9997Bioactive proteins from Solanaceae as quorum sensing inhibitors against virulence in Pseudomonas aeruginosa. Cell-to-cell communication or quorum sensing (QS) is a generic event in bacteria that is used to coordinate gene expression among local populations. The phenomenon of QS depends on the fact that presence of sufficient bacteria ascertains a threshold level of autoinducer concentration that allows bacteria to sense a critical cell mass and to activate or repress target genes. Thus, QS has been an attractive target for the development of anti-infective strategies that are not based on the use of antibiotics. Several anti-QS approaches have been demonstrated including natural products from plant-based secondary metabolites. However, the role of plant bioactive proteins as an anti-QS peptide is yet to be deciphered. Against a backdrop of ever-increasing antibiotic resistant pathogens, there is a strong need for development of alternative therapeutic strategies. Thus, our hypothesis is that bioactive proteins from the plant family Solanaceae are quorum quenching molecules that can be exploited to develop a therapeutic strategy against virulence. We presume that bioactive proteins will inactivate or inhibit or degrade QS signals from bacteria to prevent cell-to-cell communication and thus inhibit development of virulence in Pseudomonas aeruginosa. Further, the use of proteins as quorum quenchers will delay the bacteria to develop resistance against these quenching molecules.201525777471
9166190.9997Mechanisms of Inhibition of Quorum Sensing as an Alternative for the Control of E. coli and Salmonella. Quorum sensing (QS) is a process of cell-cell communication for bacteria such as E. coli and Salmonella that cause foodborne diseases, with the production, release, and detection of autoinducer (AI) molecules that participate in the regulation of virulence genes. All of these proteins are useful in coordinating collective behavior, the expression of virulence factors, and the pathogenicity of Gram-negative bacteria. In this work, we review the natural or synthetic inhibitor molecules of QS that inactivate the autoinducer and block QS regulatory proteins in E. coli and Salmonella. Furthermore, we describe mechanisms of QS inhibitors (QSIs) that act as competitive inhibitors, being a useful tool for preventing virulence gene expression through the downregulation of AI-2 production pathways and the disruption of signal uptake. In addition, we showed that QSIs have negative regulatory activity of genes related to bacterial biofilm formation on clinical artifacts, which confirms the therapeutic potential of QSIs in the control of infectious pathogens. Finally, we discuss resistance to QSIs, the design of next-generation QSIs, and how these molecules can be leveraged to provide a new antivirulence therapy to combat diseases caused by E. coli or Salmonella.202235630329