Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Targeting bacterial membrane function: an underexploited mechanism for treating persistent infections.

ABSTRACT: Persistent infections involving slow-growing or non-growing bacteria are hard to treat with antibiotics that target biosynthetic processes in growing cells. Consequently, there is a need for antimicrobials that can treat infections containing dormant bacteria. In this Review, we discuss the emerging concept that disrupting the bacterial membrane bilayer or proteins that are integral to membrane function (including membrane potential and energy metabolism) in dormant bacteria is a strategy for treating persistent infections. The clinical applicability of these approaches is exemplified by the efficacy of lipoglycopeptides that damage bacterial membranes and of the diarylquinoline TMC207, which inhibits membrane-bound ATP synthase. Despite some drawbacks, membrane-active agents form an important new means of eradicating recalcitrant, non-growing bacteria.

SUBMITTER: Hurdle JG

PROVIDER: S-EPMC3496266 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Targeting bacterial membrane function: an underexploited mechanism for treating persistent infections.

Hurdle Julian G JG O'Neill Alex J AJ Chopra Ian I Lee Richard E RE

Nature reviews. Microbiology 20110101 1

Persistent infections involving slow-growing or non-growing bacteria are hard to treat with antibiotics that target biosynthetic processes in growing cells. Consequently, there is a need for antimicrobials that can treat infections containing dormant bacteria. In this Review, we discuss the emerging concept that disrupting the bacterial membrane bilayer or proteins that are integral to membrane function (including membrane potential and energy metabolism) in dormant bacteria is a strategy for tr ...[more]

PMID: 21164535

Similar Datasets

Decomposing virulence to understand bacterial clearance in persistent infections.

Project description:Following an infection, hosts cannot always clear the pathogen, instead either dying or surviving with a persistent infection. Such variation is ecologically and evolutionarily important because it can affect infection prevalence and transmission, and virulence evolution. However, the factors causing variation in infection outcomes, and the relationship between clearance and virulence are not well understood. Here we show that sustained persistent infection and clearance are both possible outcomes across bacterial species showing a range of virulence in Drosophila melanogaster. Variation in virulence arises because of differences in the two components of virulence: bacterial infection intensity inside the host (exploitation), and the amount of damage caused per bacterium (per parasite pathogenicity). As early-phase exploitation increased, clearance rates later in the infection decreased, whereas there was no apparent effect of per parasite pathogenicity on clearance rates. Variation in infection outcomes is thereby determined by how virulence - and its components - relate to the rate of pathogen clearance. Taken together we demonstrate that the virulence decomposition framework is broadly applicable and can provide valuable insights into host-pathogen interactions.

| S-EPMC9418333 | biostudies-literature

DNA vaccines for targeting bacterial infections.

Project description:DNA vaccination has been of great interest since its discovery in the 1990s due to its ability to elicit both humoral and cellular immune responses. DNA vaccines consist of a DNA plasmid containing a transgene that encodes the sequence of a target protein from a pathogen under the control of a eukaryotic promoter. This revolutionary technology has proven to be effective in animal models and four DNA vaccine products have recently been approved for veterinary use. Although few DNA vaccines against bacterial infections have been tested, the results are encouraging. Because of their versatility, safety and simplicity a wider range of organisms can be targeted by these vaccines, which shows their potential advantages to public health. This article describes the mechanism of action of DNA vaccines and their potential use for targeting bacterial infections. In addition, it provides an updated summary of the methods used to enhance immunogenicity from codon optimization and adjuvants to delivery techniques including electroporation and use of nanoparticles.

| S-EPMC2962930 | biostudies-literature

New paradigms for understanding and step changes in treating active and chronic, persistent apicomplexan infections.

Project description:Toxoplasma gondii, the most common parasitic infection of human brain and eye, persists across lifetimes, can progressively damage sight, and is currently incurable. New, curative medicines are needed urgently. Herein, we develop novel models to facilitate drug development: EGS strain T. gondii forms cysts in vitro that induce oocysts in cats, the gold standard criterion for cysts. These cysts highly express cytochrome b. Using these models, we envisioned, and then created, novel 4-(1H)-quinolone scaffolds that target the cytochrome bc1 complex Qi site, of which, a substituted 5,6,7,8-tetrahydroquinolin-4-one inhibits active infection (IC50, 30 nM) and cysts (IC50, 4 μM) in vitro, and in vivo (25 mg/kg), and drug resistant Plasmodium falciparum (IC50, <30 nM), with clinically relevant synergy. Mutant yeast and co-crystallographic studies demonstrate binding to the bc1 complex Qi site. Our results have direct impact on improving outcomes for those with toxoplasmosis, malaria, and ~2 billion persons chronically infected with encysted bradyzoites.

| S-EPMC4944145 | biostudies-literature

Epigenetic regulation in bacterial infections: targeting histone deacetylases.

Project description:Pathogens have developed sophisticated strategies to evade the immune response, among which manipulation of host cellular epigenetic mechanisms plays a prominent role. In the last decade, modulation of histone acetylation in host cells has emerged as an efficient strategy of bacterial immune evasion. Virulence factors and metabolic products of pathogenic microorganisms alter expression and activity of histone acetyltransferases (HATs) and histone deacetylases (HDACs) to suppress transcription of host defense genes through epigenetic changes in histone acetylation marks. This new avenue of pathogen-host interactions is particularly important in light of introduction of HDAC inhibitors into clinical practice. Considerable effort is currently being applied to better understand the effects of HDAC inhibitors on the quality of immune responses to pathogens and to characterize the therapeutic potential of these compounds in microbial infections. In this review, we will discuss the recently discovered mechanisms utilized by bacteria to facilitate their survival within infected hosts through subversion of the host acetylation system and the effects of acetylation modulators, including HDAC inhibitors and bromodomain-containing BET protein inhibitors, on innate immune responses against microbial pathogens. Integration of these two lines of experimental evidence provides critical information on the perspectives of epigenetic therapies targeting protein acetylation in infectious diseases.

| S-EPMC6109591 | biostudies-literature

Replication defective viral products exploit a cellular pro-survival mechanism to establish persistent infections

Project description:Replication defective viral genomes (DVGs) generated during virus replication are the primary triggers of antiviral immunity in many infections. However, DVGs also provide viruses with an evolutionary advantage by facilitating virus persistence. Why and how DVGs and the host interact to achieve these two divergent functions remains unknown. We report that DVGs engage a MAVS-mediated antiviral response that promotes apoptosis on highly infected cells while protecting cells dominated by DVGs from death. We find that MAVS signaling leads to the expression of TNF and of the pro-survival TNFR2/TRAF1 proteins. TNF induces apoptosis of infected cells lacking DVGs, while its signaling in cells enriched in DVGs promotes their survival. These results identify DVGs as pivotal for virus-host co-existence and reveal a MAVS-mediated axis that while promoting the death of infected cells, protects those cells producing toxic cytokines from apoptosis, thereby facilitating viral persistence.

2017-08-01 | GSE96774 | GEO

Architecture and conservation of the bacterial DNA replication machinery, an underexploited drug target.

Project description:New antibiotics with novel modes of action are required to combat the growing threat posed by multi-drug resistant bacteria. Over the last decade, genome sequencing and other high-throughput techniques have provided tremendous insight into the molecular processes underlying cellular functions in a wide range of bacterial species. We can now use these data to assess the degree of conservation of certain aspects of bacterial physiology, to help choose the best cellular targets for development of new broad-spectrum antibacterials. DNA replication is a conserved and essential process, and the large number of proteins that interact to replicate DNA in bacteria are distinct from those in eukaryotes and archaea; yet none of the antibiotics in current clinical use acts directly on the replication machinery. Bacterial DNA synthesis thus appears to be an underexploited drug target. However, before this system can be targeted for drug design, it is important to understand which parts are conserved and which are not, as this will have implications for the spectrum of activity of any new inhibitors against bacterial species, as well as the potential for development of drug resistance. In this review we assess similarities and differences in replication components and mechanisms across the bacteria, highlight current progress towards the discovery of novel replication inhibitors, and suggest those aspects of the replication machinery that have the greatest potential as drug targets.

| S-EPMC3290774 | biostudies-literature

Co-translational protein targeting to the bacterial membrane.

Project description:Co-translational protein targeting by the Signal Recognition Particle (SRP) is an essential cellular pathway that couples the synthesis of nascent proteins to their proper cellular localization. The bacterial SRP, which contains the minimal ribonucleoprotein core of this universally conserved targeting machine, has served as a paradigm for understanding the molecular basis of protein localization in all cells. In this review, we highlight recent biochemical and structural insights into the molecular mechanisms by which fundamental challenges faced by protein targeting machineries are met in the SRP pathway. Collectively, these studies elucidate how an essential SRP RNA and two regulatory GTPases in the SRP and SRP receptor (SR) enable this targeting machinery to recognize, sense and respond to its biological effectors, i.e. the cargo protein, the target membrane and the translocation machinery, thus driving efficient and faithful co-translational protein targeting. This article is part of a Special Issue entitled: Protein trafficking and secretion in bacteria. Guest Editors: Anastassios Economou and Ross Dalbey.

| S-EPMC3999308 | biostudies-literature

Bacterial secretins: Mechanisms of assembly and membrane targeting.

Project description:Secretion systems are employed by bacteria to transport macromolecules across membranes without compromising their integrities. Processes including virulence, colonization, and motility are highly dependent on the secretion of effector molecules toward the immediate cellular environment, and in some cases, into the host cytoplasm. In Type II and Type III secretion systems, as well as in Type IV pili, homomultimeric complexes known as secretins form large pores in the outer bacterial membrane, and the localization and assembly of such 1 MDa molecules often relies on pilotins or accessory proteins. Significant progress has been made toward understanding details of interactions between secretins and their partner proteins using approaches ranging from bacterial genetics to cryo electron microscopy. This review provides an overview of the mode of action of pilotins and accessory proteins for T2SS, T3SS, and T4PS secretins, highlighting recent near-atomic resolution cryo-EM secretin complex structures and underlining the importance of these interactions for secretin functionality.

| S-EPMC7096711 | biostudies-literature

Comparison of Bacterial Community Composition of Primary and Persistent Endodontic Infections Using Pyrosequencing.

Project description:IntroductionElucidating the microbial ecology of endodontic infections (EIs) is a necessary step in developing effective intracanal antimicrobials. The aim of the present study was to investigate the bacterial composition of symptomatic and asymptomatic primary and persistent infections in a Greek population using high-throughput sequencing methods.Methods16S amplicon pyrosequencing of 48 root canal bacterial samples was conducted, and sequencing data were analyzed using an oral microbiome-specific and a generic (Greengenes) database. Bacterial abundance and diversity were examined by EI type (primary or persistent), and statistical analysis was performed by using non-parametric and parametric tests accounting for clustered data.ResultsBacteroidetes was the most abundant phylum in both infection groups. Significant, albeit weak associations of bacterial diversity were found, as measured by UniFrac distances with infection type (analyses of similarity, R = 0.087, P = .005) and symptoms (analyses of similarity, R = 0.055, P = .047). Persistent infections were significantly enriched for Proteobacteria and Tenericutes compared with primary ones; at the genus level, significant differences were noted for 14 taxa, including increased enrichment of persistent infections for Lactobacillus, Streptococcus, and Sphingomonas. More but less abundant phyla were identified using the Greengenes database; among those, Cyanobacteria (0.018%) and Acidobacteria (0.007%) were significantly enriched among persistent infections. Persistent infections showed higher phylogenetic diversity (PD) (asymptomatic: PD = 9.2, standard error [SE] = 1.3; symptomatic: PD = 8.2, SE = 0.7) compared with primary infections (asymptomatic: PD = 5.9, SE = 0.8; symptomatic: PD = 7.4, SE = 1.0).ConclusionsThe present study revealed a high bacterial diversity of EI and suggests that persistent infections may have more diverse bacterial communities than primary infections.

| S-EPMC4578635 | biostudies-literature

Strategies to overcome the action of aminoglycoside-modifying enzymes for treating resistant bacterial infections.

Project description:Shortly after the discovery of the first antibiotics, bacterial resistance began to emerge. Many mechanisms give rise to resistance; the most prevalent mechanism of resistance to the aminoglycoside (AG) family of antibiotics is the action of aminoglycoside-modifying enzymes (AMEs). Since the identification of these modifying enzymes, many efforts have been put forth to prevent their damaging alterations of AGs. These diverse strategies are discussed within this review, including: creating new AGs that are unaffected by AMEs; developing inhibitors of AMEs to be co-delivered with AGs; or regulating AME expression. Modern high-throughput methods as well as drug combinations and repurposing are highlighted as recent drug-discovery efforts towards fighting the increasing antibiotic resistance crisis.

| S-EPMC3819198 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data