# | Rank | Similarity | Title + Abs. | Year | PMID |
|---|---|---|---|---|---|
| 0 | 1 | 2 | 3 | 4 | 5 |
| 8436 | 0 | 0.9811 | NIR-Activated Hydrogel with Dual-Enhanced Antibiotic Effectiveness for Thorough Elimination of Antibiotic-Resistant Bacteria. Antibiotic resistance has become a critical health crisis globally. Traditional strategies using antibiotics can lead to drug-resistance, while inorganic antimicrobial agents can cause severe systemic toxicity. Here, we have developed a dual-antibiotic hydrogel delivery system (PDA-Ag@Levo/CMCS), which can achieve controlled release of clinical antibiotics levofloxacin (Levo) and classic nanoscale antibiotic silver nanoparticles (AgNPs), effectively eliminating drug-resistant P. aeruginosa. Benefiting from the photothermal (PTT) effect of polydopamine (PDA), the local high temperature generated by PDA-Ag@Levo/CMCS can quickly kill bacteria through continuous and responsive release of dual-antibiotics to restore sensitivity to ineffective antibiotics. Moreover, AgNPs could significantly improve the efficiency of traditional antibiotics by disrupting bacterial membranes and reducing their toxicity to healthy tissues. A clever combination of PTT and drug-combination therapy can effectively eliminate biofilms and drug-resistant bacteria. Mechanism studies have shown that PDA-Ag@Levo might eliminate drug-resistant P. aeruginosa by disrupting biofilm formation and protein synthesis, and inhibit the resistance mutation of P. aeruginosa by promoting the expression of related genes, such as rpoS, dinB, and mutS. Collectively, the synergistic effect of this dual-antibiotic hydrogel combined with PTT provides a creative strategy for eliminating drug-resistant bacteria in chronic infection wounds. | 2025 | 39760335 |
| 9094 | 1 | 0.9807 | Pathogen-Specific Polymeric Antimicrobials with Significant Membrane Disruption and Enhanced Photodynamic Damage To Inhibit Highly Opportunistic Bacteria. Highly pathogenic Gram-negative bacteria and their drug resistance are a severe public health threat with high mortality. Gram-negative bacteria are hard to kill due to the complex cell envelopes with low permeability and extra defense mechanisms. It is challenging to treat them with current strategies, mainly including antibiotics, peptides, polymers, and some hybrid materials, which still face the issue of drug resistance, limited antibacterial selectivity, and severe side effects. Together with precise bacteria targeting, synergistic therapeutic modalities, including physical membrane damage and photodynamic eradication, are promising to combat Gram-negative bacteria. Herein, pathogen-specific polymeric antimicrobials were formulated from amphiphilic block copolymers, poly(butyl methacrylate)- b-poly(2-(dimethylamino) ethyl methacrylate- co-eosin)- b-ubiquicidin, PBMA- b-P(DMAEMA- co-EoS)-UBI, in which pathogen-targeting peptide ubiquicidin (UBI) was tethered in the hydrophilic chain terminal, and Eosin-Y was copolymerized in the hydrophilic block. The micelles could selectively adhere to bacteria instead of mammalian cells, inserting into the bacteria membrane to induce physical membrane damage and out-diffusion of intracellular milieu. Furthermore, significant in situ generation of reactive oxygen species was observed upon light irradiation, achieving further photodynamic eradication. Broad-spectrum bacterial inhibition was demonstrated for the polymeric antimicrobials, especially highly opportunistic Gram-negative bacteria, such as Pseudomona aeruginosa ( P. aeruginosa) based on the synergy of physical destruction and photodynamic therapy, without detectable resistance. In vivo P. aeruginosa-infected knife injury model and burn model both proved good potency of bacteria eradication and promoted wound healing, which was comparable with commercial antibiotics, yet no risk of drug resistance. It is promising to hurdle the infection and resistance suffered from highly opportunistic bacteria. | 2019 | 30632740 |
| 8190 | 2 | 0.9804 | Identification 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. | 2015 | 25968646 |
| 8189 | 3 | 0.9803 | Engineering nanoparticles to silence bacterial communication. The alarming spread of bacterial resistance to traditional antibiotics has warranted the study of alternative antimicrobial agents. Quorum sensing (QS) is a chemical cell-to-cell communication mechanism utilized by bacteria to coordinate group behaviors and establish infections. QS is integral to bacterial survival, and therefore provides a unique target for antimicrobial therapy. In this study, silicon dioxide nanoparticles (Si-NP) were engineered to target the signaling molecules [i.e., acylhomoserine lactones (HSLs)] used for QS in order to halt bacterial communication. Specifically, when Si-NP were surface functionalized with β-cyclodextrin (β-CD), then added to cultures of bacteria (Vibrio fischeri), whose luminous output depends upon HSL-mediated QS, the cell-to-cell communication was dramatically reduced. Reductions in luminescence were further verified by quantitative polymerase chain reaction (qPCR) analyses of luminescence genes. Binding of HSLs to Si-NPs was examined using nuclear magnetic resonance (NMR) spectroscopy. The results indicated that by delivering high concentrations of engineered NPs with associated quenching compounds, the chemical signals were removed from the immediate bacterial environment. In actively-metabolizing cultures, this treatment blocked the ability of bacteria to communicate and regulate QS, effectively silencing and isolating the cells. Si-NPs provide a scaffold and critical stepping-stone for more pointed developments in antimicrobial therapy, especially with regard to QS-a target that will reduce resistance pressures imposed by traditional antibiotics. | 2015 | 25806030 |
| 8487 | 4 | 0.9803 | Mechanisms of nano zero-valent iron in enhancing dibenzofuran degradation by a Rhodococcus sp.: Trade-offs between ATP production and protection against reactive oxygen species. Nano zero-valent iron (nZVI) can enhance pollutants biodegradation, but it displays toxicity towards microorganisms. Gram-positive (G(+)) bacteria exhibit greater resistance to nZVI than Gram-negative bacteria. However, mechanisms of nZVI accelerating pollutants degradation by G(+) bacteria remain unclear. Herein, we explored effects of nZVI on a G(+) bacterium, Rhodococcus sp. strain p52, and mechanisms by which nZVI accelerates biodegradation of dibenzofuran, a typical polycyclic aromatic compound. Electron microscopy and energy dispersive spectroscopy analysis revealed that nZVI could penetrate cell membranes, which caused damage and growth inhibition. nZVI promoted dibenzofuran biodegradation at certain concentrations, while higher concentration functioned later due to the delayed reactive oxygen species (ROS) mitigation. Transcriptomic analysis revealed that cells adopted response mechanisms to handle the elevated ROS induced by nZVI. ATP production was enhanced by accelerated dibenzofuran degradation, providing energy for protein synthesis related to antioxidant stress and damage repair. Meanwhile, electron transport chain (ETC) was adjusted to mitigate ROS accumulation, which involved downregulating expression of ETC complex I-related genes, as well as upregulating expression of the genes for the ROS-scavenging cytochrome bd complex and ETC complex II. These findings revealed the mechanisms underlying nZVI-enhanced biodegradation by G(+) bacteria, offering insights into optimizing bioremediation strategies involving nZVI. | 2025 | 39549579 |
| 9144 | 5 | 0.9802 | Metal nanoparticles: understanding the mechanisms behind antibacterial activity. As the field of nanomedicine emerges, there is a lag in research surrounding the topic of nanoparticle (NP) toxicity, particularly concerned with mechanisms of action. The continuous emergence of bacterial resistance has challenged the research community to develop novel antibiotic agents. Metal NPs are among the most promising of these because show strong antibacterial activity. This review summarizes and discusses proposed mechanisms of antibacterial action of different metal NPs. These mechanisms of bacterial killing include the production of reactive oxygen species, cation release, biomolecule damages, ATP depletion, and membrane interaction. Finally, a comprehensive analysis of the effects of NPs on the regulation of genes and proteins (transcriptomic and proteomic) profiles is discussed. | 2017 | 28974225 |
| 9160 | 6 | 0.9802 | Interference 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. | 2018 | 29563876 |
| 8134 | 7 | 0.9801 | Sweet scents from good bacteria: Case studies on bacterial volatile compounds for plant growth and immunity. Beneficial bacteria produce diverse chemical compounds that affect the behavior of other organisms including plants. Bacterial volatile compounds (BVCs) contribute to triggering plant immunity and promoting plant growth. Previous studies investigated changes in plant physiology caused by in vitro application of the identified volatile compounds or the BVC-emitting bacteria. This review collates new information on BVC-mediated plant-bacteria airborne interactions, addresses unresolved questions about the biological relevance of BVCs, and summarizes data on recently identified BVCs that improve plant growth or protection. Recent explorations of bacterial metabolic engineering to alter BVC production using heterologous or endogenous genes are introduced. Molecular genetic approaches can expand the BVC repertoire of beneficial bacteria to target additional beneficial effects, or simply boost the production level of naturally occurring BVCs. The effects of direct BVC application in soil are reviewed and evaluated for potential large-scale field and agricultural applications. Our review of recent BVC data indicates that BVCs have great potential to serve as effective biostimulants and bioprotectants even under open-field conditions. | 2016 | 26177913 |
| 9026 | 8 | 0.9801 | Citral and its derivatives inhibit quorum sensing and biofilm formation in Chromobacterium violaceum. With an upsurge in multidrug resistant bacteria backed by biofilm defence armours, there is a desperate need of new antibiotics with a non-traditional mechanism of action. Targeting bacteria by misguiding them or halting their communication is a new approach that could offer a new way to combat the multidrug resistance problem. Quorum sensing is considered to be the achilles heel of bacteria that has a lot to offer. Since, both quorum sensing and biofilm formation have been related to drug resistance and pathogenicity, in this study we synthesised new derivatives of citral with antiquorum sensing and biofilm disrupting properties. We previously reported antimicrobial and antiquorum sensing activity of citral and herein we report the synthesis and evaluation of citral and its derivatives (CD1-CD3) for antibacterial, antibiofilm and antiquorum sensing potential against Chromobacterium violaceum using standard methods. Preliminary results revealed that CD1 is the most active of all the derivatives. Qualitative and quantitative evaluation of antiquorum sensing activity at sub-inhibitory concentrations of these compounds also revealed high activity for CD1 followed by CD2, CD3 and citral. These compounds also inhibit biofilm formation at subinhibitory concentrations without causing any bacterial growth inhibition. These results were replicated by RT-qPCR with down regulation of the quorum sensing genes when C. violaceum was treated with these test compounds. Overall, the results are quite encouraging, revealing that biofilm and quorum sensing are interrelated processes and also indicating the potential of these derivatives to impede bacterial communication and biofilm formation. | 2021 | 33392626 |
| 8437 | 9 | 0.9800 | Tocopherol polyethylene glycol succinate-modified hollow silver nanoparticles for combating bacteria-resistance. Multiple drug resistance and the increase in the appearance of superbugs together with the exceedingly scant development of new potent antibiotic drugs pose an urgent global medical threat and imminent public security crisis. In the present study, we fabricated well-dispersed tocopherol polyethylene glycol succinate (TPGS)-capped silver nanoparticles (AgNPs) of about 10 nm in size. The hollow structure of the TPGS-capped AgNPs (TPGS/AgNPs) was confirmed and applied to load antibiotics. The TPGS/AgNPs proved to be able to cross the bacterial cell wall and penetrate into bacteria, thereby delivering more of the antibiotic to the interior of bacteria and thus enhancing the in vitro antibacterial effect of the antibiotic, even overcoming the drug-resistance in drug-resistant E. coli and Acinetobacter baumannii. It was found that the TPGS modification in the TPGS/AgNPs could decrease the activity of the efflux pumps AdeABC and AdeIJK in drug-resistant Acinetobacter baumannii via inhibiting the efflux pump genes adeB and adeJ, thus increasing the accumulation of the delivered antibiotic and overcoming the drug-resistance. Tigecycline delivered by TPGS/AgNPs could effectively antagonize drug-resistance in an acute peritonitis model mice, thereby increasing the survival rate and alleviating the inflammatory response. TPGS/AgNPs were developed as a novel and effective antibiotic delivery system and TPGS was demonstrated to have great potential as a pharmaceutical excipient for use in drug-resistant infection therapy. | 2019 | 30968093 |
| 9169 | 10 | 0.9797 | Interference 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. | 2013 | 23720655 |
| 9167 | 11 | 0.9797 | Bioactive 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. | 2015 | 25777471 |
| 9164 | 12 | 0.9797 | Quorum quenching: role of nanoparticles as signal jammers in Gram-negative bacteria. Quorum sensing (QS) is a cell density dependent regulatory process that uses signaling molecules to manage the expression of virulence genes and biofilm formation. The study of QS inhibitors has emerged as one of the most fascinating areas of research to discover novel antimicrobial agents. Compounds that block QS have become candidates as unusual antimicrobial agents, as they are leading players in the regulation of virulence of drug-resistant pathogens. Metal and metal oxide nanoparticles offer novel alternatives to combat antibiotic resistance in Gram-negative bacteria aiming their capacity as QS inhibitors. This review provides an insight into the quorum quenching potential of metal and metal oxide nanoparticles by targeting QS regulated virulence of Gram-negative bacteria. | 2019 | 30539663 |
| 805 | 13 | 0.9796 | LexR Positively Regulates the LexABC Efflux Pump Involved in Self-Resistance to the Antimicrobial Di-N-Oxide Phenazine in Lysobacter antibioticus. Myxin, a di-N-oxide phenazine isolated from the soil bacterium Lysobacter antibioticus, exhibits potent activity against various microorganisms and has the potential to be developed as an agrochemical. Antibiotic-producing microorganisms have developed self-resistance mechanisms to protect themselves from autotoxicity. Antibiotic efflux is vital for such protection. Recently, we identified a resistance-nodulation-division (RND) efflux pump, LexABC, involved in self-resistance against myxin in L. antibioticus. Expression of its genes, lexABC, was induced by myxin and was positively regulated by the LysR family transcriptional regulator LexR. The molecular mechanisms, however, have not been clear. Here, LexR was found to bind to the lexABC promoter region to directly regulate expression. Moreover, myxin enhanced this binding. Molecular docking and surface plasmon resonance analysis showed that myxin bound LexR with valine and lysine residues at positions 146 (V146) and 195 (K195), respectively. Furthermore, mutation of K195 in vivo led to downregulation of the gene lexA. These results indicated that LexR sensed and bound with myxin, thereby directly activating the expression of the LexABC efflux pump and increasing L. antibioticus resistance against myxin. IMPORTANCE Antibiotic-producing bacteria exhibit various sophisticated mechanisms for self-protection against their own secondary metabolites. RND efflux pumps that eliminate antibiotics from cells are ubiquitous in Gram-negative bacteria. Myxin is a heterocyclic N-oxide phenazine with potent antimicrobial and antitumor activities produced by the soil bacterium L. antibioticus. The RND pump LexABC contributes to the self-resistance of L. antibioticus against myxin. Herein, we report a mechanism involving the LysR family regulator LexR that binds to myxin and directly activates the LexABC pump. Further study on self-resistance mechanisms could help the investigation of strategies to deal with increasing bacterial antibiotic resistance and enable the discovery of novel natural products with resistance genes as selective markers. | 2023 | 37166326 |
| 8159 | 14 | 0.9796 | Quaternary Ammonium Salts: Insights into Synthesis and New Directions in Antibacterial Applications. The overuse of antibiotics has led to the emergence of a large number of antibiotic-resistant genes in bacteria, and increasing evidence indicates that a fungicide with an antibacterial mechanism different from that of antibiotics is needed. Quaternary ammonium salts (QASs) are a biparental substance with good antibacterial properties that kills bacteria through simple electrostatic adsorption and insertion into cell membranes/altering of cell membrane permeability. Therefore, the probability of bacteria developing drug resistance is greatly reduced. In this review, we focus on the synthesis and application of single-chain QASs, double-chain QASs, heterocyclic QASs, and gemini QASs (GQASs). Some possible structure-function relationships of QASs are also summarized. As such, we hope this review will provide insight for researchers to explore more applications of QASs in the field of antimicrobials with the aim of developing systems for clinical applications. | 2023 | 36748912 |
| 9155 | 15 | 0.9795 | Polyphenols and their nanoformulations as potential antibiofilm agents against multidrug-resistant pathogens. The emergence of multidrug-resistant (MDR) pathogens is a major problem in the therapeutic management of infectious diseases. Among the bacterial resistance mechanisms is the development of an enveloped protein and polysaccharide-hydrated matrix called a biofilm. Polyphenolics have demonstrated beneficial antibacterial effects. Phenolic compounds mediate their antibiofilm effects via disruption of the bacterial membrane, deprivation of substrate, protein binding, binding to adhesion complex, viral fusion blockage and interactions with eukaryotic DNA. However, these compounds have limitations of chemical instability, low bioavailability, poor water solubility and short half-lives. Nanoformulations offer a promising solution to overcome these challenges by enhancing their antibacterial potential. This review summarizes the antibiofilm role of polyphenolics, their underlying mechanisms and their potential role as resistance-modifying agents. | 2024 | 38305223 |
| 8160 | 16 | 0.9795 | Quorum Sensing in Gram-Negative Bacteria: Strategies to Overcome Antibiotic Resistance in Ocular Infections. Truly miraculous medications and antibiotics have helped save untold millions of lives. Antibiotic resistance, however, is a significant issue related to health that jeopardizes the effectiveness of antibiotics and could harm everyone's health. Bacteria, not humans or animals, become antibiotic-resistant. Bacteria use quorum-sensing communication routes to manage an assortment of physiological exercises. Quorum sensing is significant for appropriate biofilm development. Antibiotic resistance occurs when bacteria establish a biofilm on a surface, shielding them from the effects of infection-fighting drugs. Acylated homoserine lactones are used as autoinducers by gram-negative microscopic organisms to impart. However, antibiotic resistance among ocular pathogens is increasing worldwide. Bacteria are a significant contributor to ocular infections around the world. Gram-negative microscopic organisms are dangerous to ophthalmic tissues. This review highlights the use of elective drug targets and treatments, for example, combinational treatment, to vanquish antibiotic-resistant bacteria. Also, it briefly portrays anti-biotic resistance brought about by gram-negative bacteria and approaches to overcome resistance with the help of quorum sensing inhibitors and nanotechnology as a promising medication conveyance approach to give insurance of anti-microbials and improve pathways for the administration of inhibitors of quorum sensing with a blend of anti-microbials to explicit target destinations and penetration through biofilms for treatment of ocular infections. It centres on the methodologies to sidestep the confinements of ocular anti-biotic delivery with new visual innovation. | 2024 | 37497706 |
| 746 | 17 | 0.9795 | Novel 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. | 2025 | 41083642 |
| 9168 | 18 | 0.9795 | Novel 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. | 2007 | 17402841 |
| 9161 | 19 | 0.9795 | In Silico Evaluation of the Impacts of Quorum Sensing Inhibition (QSI) on Strain Competition and Development of QSI Resistance. As understanding of bacterial regulatory systems and pathogenesis continues to increase, QSI has been a major focus of research. However, recent studies have shown that mechanisms of resistance to quorum sensing (QS) inhibitors (QSIs) exist, calling into question their clinical value. We propose a computational framework that considers bacteria genotypes relative to QS genes and QS-regulated products including private, quasi-public, and public goods according to their impacts on bacterial fitness. Our results show (1) QSI resistance spreads when QS positively regulates the expression of private or quasi-public goods. (2) Resistance to drugs targeting secreted compounds downstream of QS for a mix of private, public, and quasi-public goods also spreads. (3) Changing the micro-environment during treatment with QSIs may decrease the spread of resistance. At fundamental-level, our simulation framework allows us to directly quantify cell-cell interactions and biofilm dynamics. Practically, the model provides a valuable tool for the study of QSI-based therapies, and the simulations reveal experimental paths that may guide QSI-based therapies in a manner that avoids or decreases the spread of QSI resistance. | 2016 | 27734907 |