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74600.9869Novel antimicrobial 3-phenyl-4-phenoxypyrazole derivatives target cell wall lipid intermediates with low mammalian cytotoxicity. The growing crisis of antimicrobial resistance (AMR) underscores the critical need for innovative antimicrobial discoveries. Novel antibiotics targeting the bacterial cell wall remain an attractive area of research, due to their conservation and essentiality in bacteria and their absence in eukaryotic cells. Antibiotics targeting lipid II are of special interest due to the reduced potential for target modification of lipid components and their surface accessibility to inhibitors. In this study, we identified 3-phenyl-4-phenoxypyrazole analogues named PYO12 and PYO12a with bactericidal activity against gram-positive bacteria and low cytotoxicity for different types of mammalian cells. Gram-negative bacteria were resistant to PYO12 activity through extrusion of this compound via efflux pumps. Exposure to PYO12 induces expression of genes involved in resistance to antimicrobials targeting the cell wall, suggesting that PYO12 acts via binding to lipid II or other lipid intermediates involved in peptidoglycan or teichoic acid biosynthesis. Antagonism of PYO12 antibacterial activity by undecaprenyl-pyrophosphate supports the idea that PYO12 may bind to the lipid moiety of lipid II blocking the shuttling of peptidoglycan precursors across the cytoplasmic membrane. These findings open opportunities to further develop these compounds as antibiotics targeting bacterial cell wall synthesis.202541083642
62010.9864Transcriptomic Responses and Survival Mechanisms of Staphylococci to the Antimicrobial Skin Lipid Sphingosine. Sphingosines are antimicrobial lipids that form part of the innate barrier to skin colonization by microbes. Sphingosine deficiencies can result in increased epithelial infections by bacteria including Staphylococcus aureus. Recent studies have focused on the potential use of sphingosine resistance or its potential mechanisms. We used RNA-Seq to identify the common d-sphingosine transcriptomic response of the transient skin colonizer S. aureus and the dominant skin coloniser S. epidermidis. A common d-sphingosine stimulon was identified that included downregulation of the SaeSR two-component system (TCS) regulon and upregulation of both the VraSR TCS and CtsR stress regulons. We show that the PstSCAB phosphate transporter, and VraSR offer intrinsic resistance to d-sphingosine. Further, we demonstrate increased sphingosine resistance in these staphylococci evolves readily through mutations in genes encoding the FarE-FarR efflux/regulator proteins. The ease of selecting mutants with resistance to sphingosine may impact upon staphylococcal colonization of skin where the lipid is present and have implications with topical therapeutic applications.202234902269
72820.9862Surviving Reactive Chlorine Stress: Responses of Gram-Negative Bacteria to Hypochlorous Acid. Sodium hypochlorite (NaOCl) and its active ingredient, hypochlorous acid (HOCl), are the most commonly used chlorine-based disinfectants. HOCl is a fast-acting and potent antimicrobial agent that interacts with several biomolecules, such as sulfur-containing amino acids, lipids, nucleic acids, and membrane components, causing severe cellular damage. It is also produced by the immune system as a first-line of defense against invading pathogens. In this review, we summarize the adaptive responses of Gram-negative bacteria to HOCl-induced stress and highlight the role of chaperone holdases (Hsp33, RidA, Cnox, and polyP) as an immediate response to HOCl stress. We also describe the three identified transcriptional regulators (HypT, RclR, and NemR) that specifically respond to HOCl. Besides the activation of chaperones and transcriptional regulators, the formation of biofilms has been described as an important adaptive response to several stressors, including HOCl. Although the knowledge on the molecular mechanisms involved in HOCl biofilm stimulation is limited, studies have shown that HOCl induces the formation of biofilms by causing conformational changes in membrane properties, overproducing the extracellular polymeric substance (EPS) matrix, and increasing the intracellular concentration of cyclic-di-GMP. In addition, acquisition and expression of antibiotic resistance genes, secretion of virulence factors and induction of the viable but nonculturable (VBNC) state has also been described as an adaptive response to HOCl. In general, the knowledge of how bacteria respond to HOCl stress has increased over time; however, the molecular mechanisms involved in this stress response is still in its infancy. A better understanding of these mechanisms could help understand host-pathogen interactions and target specific genes and molecules to control bacterial spread and colonization.202032796669
73030.9861How intracellular bacteria survive: surface modifications that promote resistance to host innate immune responses. Bacterial pathogens regulate the expression of virulence factors in response to environmental signals. In the case of salmonellae, many virulence factors are regulated via PhoP/PhoQ, a two-component signal transduction system that is repressed by magnesium and calcium in vitro. PhoP/PhoQ-activated genes promote intracellular survival within macrophages, whereas PhoP-repressed genes promote entrance into epithelial cells and macrophages by macropinocytosis and stimulate epithelial cell cytokine production. PhoP-activated genes include those that alter the cell envelope through structural alterations of lipopolysaccharide and lipid A, the bioactive component of lipopolysaccharide. PhoP-activated changes in the bacterial envelope likely promote intracellular survival by increasing resistance to host cationic antimicrobial peptides and decreasing host cell cytokine production.199910081503
61140.9860The Staphylococcus aureus FASII bypass escape route from FASII inhibitors. Antimicrobials targeting the fatty acid synthesis (FASII) pathway are being developed as alternative treatments for bacterial infections. Emergence of resistance to FASII inhibitors was mainly considered as a consequence of mutations in the FASII target genes. However, an alternative and efficient anti-FASII resistance strategy, called here FASII bypass, was uncovered. Bacteria that bypass FASII incorporate exogenous fatty acids in membrane lipids, and thus dispense with the need for FASII. This strategy is used by numerous Gram-positive low GC % bacteria, including streptococci, enterococci, and staphylococci. Some bacteria repress FASII genes once fatty acids are available, and "constitutively" shift to FASII bypass. Others, such as the major pathogen Staphylococcus aureus, can undergo high frequency mutations that favor FASII bypass. This capacity is particularly relevant during infection, as the host supplies the fatty acids needed for bacteria to bypass FASII and thus become resistant to FASII inhibitors. Screenings for anti-FASII resistance in the presence of exogenous fatty acids confirmed that FASII bypass confers anti-FASII resistance among clinical and veterinary isolates. Polymorphisms in S. aureus FASII initiation enzymes favor FASII bypass, possibly by increasing availability of acyl-carrier protein, a required intermediate. Here we review FASII bypass and consequences in light of proposed uses of anti-FASII to treat infections, with a focus on FASII bypass in S. aureus.201728728970
58950.9860Insulin Signaling and Insulin Resistance Facilitate Trained Immunity in Macrophages Through Metabolic and Epigenetic Changes. Adaptation of the innate immune system has been recently acknowledged, explaining sustained changes of innate immune responses. Such adaptation is termed trained immunity. Trained immunity is initiated by extracellular signals that trigger a cascade of events affecting cell metabolism and mediating chromatin changes on genes that control innate immune responses. Factors demonstrated to facilitate trained immunity are pathogenic signals (fungi, bacteria, viruses) as well non-pathogenic signals such as insulin, cytokines, adipokines or hormones. These signals initiate intracellular signaling cascades that include AKT kinases and mTOR as well as histone methylases and demethylases, resulting in metabolic changes and histone modifications. In the context of insulin resistance, AKT signaling is affected resulting in sustained activation of mTORC1 and enhanced glycolysis. In macrophages elevated glycolysis readily impacts responses to pathogens (bacteria, fungi) or danger signals (TLR-driven signals of tissue damage), partly explaining insulin resistance-related pathologies. Thus, macrophages lacking insulin signaling exhibit reduced responses to pathogens and altered metabolism, suggesting that insulin resistance is a state of trained immunity. Evidence from Insulin Receptor as well as IGF1Receptor deficient macrophages support the contribution of insulin signaling in macrophage responses. In addition, clinical evidence highlights altered macrophage responses to pathogens or metabolic products in patients with systemic insulin resistance, being in concert with cell culture and animal model studies. Herein, we review the current knowledge that supports the impact of insulin signaling and other insulin resistance related signals as modulators of trained immunity.201931244863
916060.9860Interference in Bacterial Quorum Sensing: A Biopharmaceutical Perspective. Numerous bacteria utilize molecular communication systems referred to as quorum sensing (QS) to synchronize the expression of certain genes regulating, among other aspects, the expression of virulence factors and the synthesis of biofilm. To achieve this process, bacteria use signaling molecules, known as autoinducers (AIs), as chemical messengers to share information. Naturally occurring strategies that interfere with bacterial signaling have been extensively studied in recent years, examining their potential to control bacteria. To interfere with QS, bacteria use quorum sensing inhibitors (QSIs) to block the action of AIs and quorum quenching (QQ) enzymes to degrade signaling molecules. Recent studies have shown that these strategies are promising routes to decrease bacterial pathogenicity and decrease biofilms, potentially enhancing bacterial susceptibility to antimicrobial agents including antibiotics and bacteriophages. The efficacy of QSIs and QQ enzymes has been demonstrated in various animal models and are now considered in the development of new medical devices against bacterial infections, including dressings, and catheters for enlarging the therapeutic arsenal against bacteria.201829563876
916770.9859Bioactive 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
902780.9859Scorpion Venom Antimicrobial Peptides Induce Siderophore Biosynthesis and Oxidative Stress Responses in Escherichia coli. The increasing development of microbial resistance to classical antimicrobial agents has led to the search for novel antimicrobials. Antimicrobial peptides (AMPs) derived from scorpion and snake venoms offer an attractive source for the development of novel therapeutics. Smp24 (24 amino acids [aa]) and Smp43 (43 aa) are broad-spectrum AMPs that have been identified from the venom gland of the Egyptian scorpion Scorpio mauruspalmatus and subsequently characterized. Using a DNA microarray approach, we examined the transcriptomic responses of Escherichia coli to subinhibitory concentrations of Smp24 and Smp43 peptides following 5 h of incubation. Seventy-two genes were downregulated by Smp24, and 79 genes were downregulated by Smp43. Of these genes, 14 genes were downregulated in common and were associated with bacterial respiration. Fifty-two genes were specifically upregulated by Smp24. These genes were predominantly related to cation transport, particularly iron transport. Three diverse genes were independently upregulated by Smp43. Strains with knockouts of differentially regulated genes were screened to assess the effect on susceptibility to Smp peptides. Ten mutants in the knockout library had increased levels of resistance to Smp24. These genes were predominantly associated with cation transport and binding. Two mutants increased resistance to Smp43. There was no cross-resistance in mutants resistant to Smp24 or Smp43. Five mutants showed increased susceptibility to Smp24, and seven mutants showed increased susceptibility to Smp43. Of these mutants, formate dehydrogenase knockout (fdnG) resulted in increased susceptibility to both peptides. While the electrostatic association between pore-forming AMPs and bacterial membranes followed by integration of the peptide into the membrane is the initial starting point, it is clear that there are numerous subsequent additional intracellular mechanisms that contribute to their overall antimicrobial effect.IMPORTANCE The development of life-threatening resistance of pathogenic bacteria to the antibiotics typically in use in hospitals and the community today has led to an urgent need to discover novel antimicrobial agents with different mechanisms of action. As an ancient host defense mechanism of the innate immune system, antimicrobial peptides (AMPs) are attractive candidates to fill that role. Scorpion venoms have proven to be a rich source of AMPs. Smp24 and Smp43 are new AMPs that have been identified from the venom gland of the Egyptian scorpion Scorpio maurus palmatus, and these peptides can kill a wide range of bacterial pathogens. By better understanding how these AMPs affect bacterial cells, we can modify their structure to make better drugs in the future.202133980680
905990.9859Validation of Suitable Carrier Molecules and Target Genes for Antisense Therapy Using Peptide-Coupled Peptide Nucleic Acids (PNAs) in Streptococci. Antisense peptide nucleic acids (PNAs) targeting genes involved in metabolism or virulence are a possible means to treat infections or to investigate pathogenic bacteria. Potential targets include essential genes, virulence factor genes, or antibiotic resistance genes. For efficient cellular uptake, PNAs can be coupled to cell-penetrating peptides (CPPs). CPPs are peptides that serve as molecular transporters and are characterized by a comparably low cytotoxicity. So far, there is only limited information about CPPs that mediate PNA uptake by Gram-positive bacteria. Here, we describe two methods to identify suitable CPP-antisense PNA conjugates, novel carrier molecules, and efficient target genes for streptococcal species and to evaluate their antimicrobial efficiency.202032430835
618100.9859A novel chemical inducer of Streptococcus quorum sensing acts by inhibiting the pheromone-degrading endopeptidase PepO. Bacteria produce chemical signals (pheromones) to coordinate behaviors across a population in a process termed quorum sensing (QS). QS systems comprising peptide pheromones and their corresponding Rgg receptors are widespread among Firmicutes and may be useful targets for manipulating microbial behaviors, like suppressing virulence. The Rgg2/3 QS circuit of the human pathogen Streptococcus pyogenes controls genes affecting resistance to host lysozyme in response to short hydrophobic pheromones (SHPs). Considering that artificial activation of a QS pathway may be as useful in the objective of manipulating bacteria as inhibiting it, we sought to identify small-molecule inducers of the Rgg2/3 QS system. We report the identification of a small molecule, P516-0475, that specifically induced expression of Rgg2/3-regulated genes in the presence of SHP pheromones at concentrations lower than typically required for QS induction. In searching for the mode of action of P516-0475, we discovered that an S. pyogenes mutant deficient in pepO, a neprilysin-like metalloendopeptidase that degrades SHP pheromones, was unresponsive to the compound. P516-0475 directly inhibited recombinant PepO in vitro as an uncompetitive inhibitor. We conclude that this compound induces QS by stabilizing SHP pheromones in culture. Our study indicates the usefulness of cell-based screens that modulate pathway activities to identify unanticipated therapeutic targets contributing to QS signaling.201829203527
622110.9858Small-Molecule Antibiotics Inhibiting tRNA-Regulated Gene Expression Is a Viable Strategy for Targeting Gram-Positive Bacteria. Bacterial infections and the rise of antibiotic resistance, especially multidrug resistance, have generated a clear need for discovery of novel therapeutics. We demonstrated that a small-molecule drug, PKZ18, targets the T-box mechanism and inhibits bacterial growth. The T-box is a structurally conserved riboswitch-like gene regulator in the 5' untranslated region (UTR) of numerous essential genes of Gram-positive bacteria. T-boxes are stabilized by cognate, unacylated tRNA ligands, allowing the formation of an antiterminator hairpin in the mRNA that enables transcription of the gene. In the absence of an unacylated cognate tRNA, transcription is halted due to the formation of a thermodynamically more stable terminator hairpin. PKZ18 targets the site of the codon-anticodon interaction of the conserved stem I and reduces T-box-controlled gene expression. Here, we show that novel analogs of PKZ18 have improved MICs, bactericidal effects against methicillin-resistant Staphylococcus aureus (MRSA), and increased efficacy in nutrient-limiting conditions. The analogs have reduced cytotoxicity against eukaryotic cells compared to PKZ18. The PKZ18 analogs acted synergistically with aminoglycosides to significantly enhance the efficacy of the analogs and aminoglycosides, further increasing their therapeutic windows. RNA sequencing showed that the analog PKZ18-22 affects expression of 8 of 12 T-box controlled genes in a statistically significant manner, but not other 5'-UTR regulated genes in MRSA. Very low levels of resistance further support the existence of multiple T-box targets for PKZ18 analogs in the cell. Together, the multiple targets, low resistance, and synergy make PKZ18 analogs promising drugs for development and future clinical applications.202033077662
9159120.9858Quorum sensing inhibitors (QSIs): a patent review (2019-2023). INTRODUCTION: The collective behavior of bacteria is regulated by Quorum Sensing (QS), in which bacteria release chemical signals and express virulence genes in a cell density-dependent manner. Quorum Sensing inhibitors (QSIs) are a large class of natural and synthetic compounds that have the potential to competitively inhibit the Quorum Sensing (QS) systems of several pathogens blocking their virulence mechanisms. They are considered promising compounds to deal with antimicrobial resistance, providing an opportunity to develop new drugs against these targets. AREAS COVERED: The present review represents a comprehensive analysis of patents and patent applications available on Espacenet and Google Patent, from 2019 to 2023 referring to the therapeutic use of Quorum Sensing inhibitors. EXPERT OPINION: Unlike classical antibiotics, which target the basic cellular metabolic processes, QSIs provide a promising alternative to attenuating virulence and pathogenicity without putting selective pressure on bacteria. The general belief is that QSIs pose no or little selective pressure on bacteria since these do not affect their growth. To date, QSIs are seen as the most promising alternative to traditional antibiotics. The next big step in this area of research is its succession to the clinical stage.202540219759
9169130.9858Interference 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
750140.9857Mutations in Genes with a Role in Cell Envelope Biosynthesis Render Gram-Negative Bacteria Highly Susceptible to the Anti-Infective Small Molecule D66. Anti-infectives include molecules that target microbes in the context of infection but lack antimicrobial activity under conventional growth conditions. We previously described D66, a small molecule that kills the Gram-negative pathogen Salmonella enterica serovar Typhimurium (S. Typhimurium) within cultured macrophages and murine tissues, with low host toxicity. While D66 fails to inhibit bacterial growth in standard media, the compound is bacteriostatic and disrupts the cell membrane voltage gradient without lysis under growth conditions that permeabilize the outer membrane or reduce efflux pump activity. To gain insights into specific bacterial targets of D66, we pursued two genetic approaches. Selection for resistance to D66 revealed spontaneous point mutations that mapped within the gmhB gene, which encodes a protein involved in the biosynthesis of the lipopolysaccharide core molecule. E. coli and S. Typhimurium gmhB mutants exhibited increased resistance to antibiotics, indicating a more robust barrier to entry. Conversely, S. Typhimurium transposon insertions in genes involved in outer membrane permeability or efflux pump activity reduced fitness in the presence of D66. Together, these observations underscore the significance of the bacterial cell envelope in safeguarding Gram-negative bacteria from small molecules.202540732029
8190150.9857Identification of Quorum-Sensing Inhibitors Disrupting Signaling between Rgg and Short Hydrophobic Peptides in Streptococci. Bacteria coordinate a variety of social behaviors, important for both environmental and pathogenic bacteria, through a process of intercellular chemical signaling known as quorum sensing (QS). As microbial resistance to antibiotics grows more common, a critical need has emerged to develop novel anti-infective therapies, such as an ability to attenuate bacterial pathogens by means of QS interference. Rgg quorum-sensing pathways, widespread in the phylum Firmicutes, employ cytoplasmic pheromone receptors (Rgg transcription factors) that directly bind and elicit gene expression responses to imported peptide signals. In the human-restricted pathogen Streptococcus pyogenes, the Rgg2/Rgg3 regulatory circuit controls biofilm development in response to the short hydrophobic peptides SHP2 and SHP3. Using Rgg-SHP as a model receptor-ligand target, we sought to identify chemical compounds that could specifically inhibit Rgg quorum-sensing circuits. Individual compounds from a diverse library of known drugs and drug-like molecules were screened for their ability to disrupt complexes of Rgg and FITC (fluorescein isothiocyanate)-conjugated SHP using a fluorescence polarization (FP) assay. The best hits were found to bind Rgg3 in vitro with submicromolar affinities, to specifically abolish transcription of Rgg2/3-controlled genes, and to prevent biofilm development in S. pyogenes without affecting bacterial growth. Furthermore, the top hit, cyclosporine A, as well as its nonimmunosuppressive analog, valspodar, inhibited Rgg-SHP pathways in multiple species of Streptococcus. The Rgg-FITC-peptide-based screen provides a platform to identify inhibitors specific for each Rgg type. Discovery of Rgg inhibitors constitutes a step toward the goal of manipulating bacterial behavior for purposes of improving health. IMPORTANCE: The global emergence of antibiotic-resistant bacterial infections necessitates discovery not only of new antimicrobials but also of novel drug targets. Since antibiotics restrict microbial growth, strong selective pressures to develop resistance emerge quickly in bacteria. A new strategy to fight microbial infections has been proposed, namely, development of therapies that decrease pathogenicity of invading organisms while not directly inhibiting their growth, thus decreasing selective pressure to establish resistance. One possible means to this goal is to interfere with chemical communication networks used by bacteria to coordinate group behaviors, which can include the synchronized expression of genes that lead to disease. In this study, we identified chemical compounds that disrupt communication pathways regulated by Rgg proteins in species of Streptococcus. Treatment of cultures of S. pyogenes with the inhibitors diminished the development of biofilms, demonstrating an ability to control bacterial behavior with chemicals that do not inhibit growth.201525968646
8210160.9857Bacterial sensing of antimicrobial peptides. Antimicrobial peptides (AMPs) form a crucial part of human innate host defense, especially in neutrophil phagosomes and on epithelial surfaces. Bacteria have a variety of efficient resistance mechanisms to human AMPs, such as efflux pumps, secreted proteases, and alterations of the bacterial cell surface that are aimed to minimize attraction of the typically cationic AMPs. In addition, bacteria have specific sensors that activate AMP resistance mechanisms when AMPs are present. The prototypical Gram-negative PhoP/PhoQ and the Gram-positive Aps AMP-sensing systems were first described and investigated in Salmonella typhimurium and Staphylococcus epidermidis, respectively. Both include a classical bacterial two-component sensor/regulator system, but show many structural, mechanistic, and functional differences. The PhoP/PhoQ regulon controls a variety of genes not necessarily limited to AMP resistance mechanisms, but apparently aimed to combat innate host defense on a broad scale. In contrast, the staphylococcal Aps system predominantly upregulates AMP resistance mechanisms, namely the D-alanylation of teichoic acids, inclusion of lysyl-phosphati-dylglycerol in the cytoplasmic membrane, and expression of the putative VraFG AMP efflux pump. Notably, both systems are crucial for virulence and represent possible targets for antimicrobial therapy.200919494583
8145170.9857Emerging role for RNA-based regulation in plant immunity. Infection by phytopathogenic bacteria triggers massive changes in plant gene expression, which are thought to be mostly a result of transcriptional reprogramming. However, evidence is accumulating that plants additionally use post-transcriptional regulation of immune-responsive mRNAs as a strategic weapon to shape the defense-related transcriptome. Cellular RNA-binding proteins regulate RNA stability, splicing or mRNA export of immune-response transcripts. In particular, mutants defective in alternative splicing of resistance genes exhibit compromised disease resistance. Furthermore, detection of bacterial pathogens induces the differential expression of small non-coding RNAs including microRNAs that impact the host defense transcriptome. Phytopathogenic bacteria in turn have evolved effector proteins to inhibit biogenesis and/or activity of cellular microRNAs. Whereas RNA silencing has long been known as an antiviral defense response, recent findings also reveal a major role of this process in antibacterial defense. Here we review the function of RNA-binding proteins and small RNA-directed post-transcriptional regulation in antibacterial defense. We mainly focus on studies that used the model system Arabidopsis thaliana and also discuss selected examples from other plants.201323163405
8273180.9856Targeting quorum sensing and competence stimulation for antimicrobial chemotherapy. Bacterial resistance to antibiotics is now a serious problem, with traditional classes of antibiotics having gradually become ineffective. New drugs are therefore needed to target and inhibit novel pathways that affect the growth of bacteria. An important feature in the survival of bacteria is that they coordinate their efforts together as a colony via secreted auto-inducing molecules. Competence stimulating peptides (CSPs) are among the quorum sensing pheromones involved in this coordination. These peptides activate a two-component system in gram-negative bacteria, binding to and activating a histidine kinase receptor called ComD, which phosphorylates a response regulator called ComE, leading to gene expression and induction of competence. Competent bacteria are able to take up exogenous DNA and incorporate it into their own genome. By this mechanism bacteria are able to acquire and share genes encoding antibiotic resistance. Despite having been studied for over 30 years, this pathway has only recently begun to be explored as a novel approach to modulating bacterial growth. Antagonists of ComD might block the signaling cascade that leads to competence, while overstimulation of ComD might also reduce bacterial growth. One possible approach to inhibiting ComD is to examine peptide sequences of CSPs that activate ComD and attempt to constrain them to bioactive conformations, likely to have higher affinity due to pre-organization for recognition by the receptor. Thus, small molecules that mimic an alpha helical epitope of CSPs, the putative ComD binding domain, have been shown here to inhibit growth of bacteria such as S. pneumoniae. Such alpha helix mimetics may be valuable clues to antibacterial chemotherapeutic agents that utilize a new mechanism to control bacterial growth.201222664089
8137190.9855Modulation of Bacterial Fitness and Virulence Through Antisense RNAs. Regulatory RNAs contribute to gene expression control in bacteria. Antisense RNAs (asRNA) are a class of regulatory RNAs that are transcribed from opposite strands of their target genes. Typically, these untranslated transcripts bind to cognate mRNAs and rapidly regulate gene expression at the post-transcriptional level. In this article, we review asRNAs that modulate bacterial fitness and increase virulence. We chose examples that underscore the variety observed in nature including, plasmid- and chromosome-encoded asRNAs, a riboswitch-regulated asRNA, and asRNAs that require other RNAs or RNA-binding proteins for stability and activity. We explore how asRNAs improve bacterial fitness and virulence by modulating plasmid acquisition and maintenance, regulating transposon mobility, increasing resistance against bacteriophages, controlling flagellar production, and regulating nutrient acquisition. We conclude with a brief discussion on how this knowledge is helping to inform current efforts to develop new therapeutics.202033747974