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Frontiers in Immunology 2023Nucleotide-binding oligomerization domain-containing proteins, NOD1 and NOD2, are cytosolic receptors that recognize dipeptides and tripeptides derived from the... (Review)
Review
Nucleotide-binding oligomerization domain-containing proteins, NOD1 and NOD2, are cytosolic receptors that recognize dipeptides and tripeptides derived from the bacterial cell wall component peptidoglycan (PGN). During the past two decades, studies have revealed several roles for NODs beyond detecting PGN fragments, including activation of an innate immune anti-viral response, NOD-mediated autophagy, and ER stress induced inflammation. Recent studies have also clarified the dynamic regulation of NODs at cellular membranes to generate specific and balanced immune responses. This review will describe how NOD1 and NOD2 detect microbes and cellular stress and detail the molecular mechanisms that regulate activation and signaling while highlighting new evidence and the impact on inflammatory disease pathogenesis.
Topics: Humans; Nod Signaling Adaptor Proteins; Nod1 Signaling Adaptor Protein; Nod2 Signaling Adaptor Protein; Inflammation; Nucleotides
PubMed: 37869013
DOI: 10.3389/fimmu.2023.1242659 -
The ISME Journal Jul 2023Although the phylum Chloroflexota is ubiquitous, its biology and evolution are poorly understood due to limited cultivability. Here, we isolated two motile, thermophilic...
Although the phylum Chloroflexota is ubiquitous, its biology and evolution are poorly understood due to limited cultivability. Here, we isolated two motile, thermophilic bacteria from hot spring sediments belonging to the genus Tepidiforma and class Dehalococcoidia within the phylum Chloroflexota. A combination of cryo-electron tomography, exometabolomics, and cultivation experiments using stable isotopes of carbon revealed three unusual traits: flagellar motility, a peptidoglycan-containing cell envelope, and heterotrophic activity on aromatics and plant-associated compounds. Outside of this genus, flagellar motility has not been observed in Chloroflexota, and peptidoglycan-containing cell envelopes have not been described in Dehalococcoidia. Although these traits are unusual among cultivated Chloroflexota and Dehalococcoidia, ancestral character state reconstructions showed flagellar motility and peptidoglycan-containing cell envelopes were ancestral within the Dehalococcoidia, and subsequently lost prior to a major adaptive radiation of Dehalococcoidia into marine environments. However, despite the predominantly vertical evolutionary histories of flagellar motility and peptidoglycan biosynthesis, the evolution of enzymes for degradation of aromatics and plant-associated compounds was predominantly horizontal and complex. Together, the presence of these unusual traits in Dehalococcoidia and their evolutionary histories raise new questions about the timing and selective forces driving their successful niche expansion into global oceans.
Topics: Phylogeny; Peptidoglycan; Bacteria; Chloroflexi; Phenotype
PubMed: 37041326
DOI: 10.1038/s41396-023-01405-0 -
Antibiotics (Basel, Switzerland) Jan 2024() with multi-drug resistance (MDR) is a major cause of serious healthcare-associated infections, leading to high morbidity and mortality. This opportunistic pathogen... (Review)
Review
() with multi-drug resistance (MDR) is a major cause of serious healthcare-associated infections, leading to high morbidity and mortality. This opportunistic pathogen is responsible for various infectious diseases, such as those seen in cystic fibrosis, ventilator-associated pneumonia, urinary tract infection, otitis externa, and burn and wound injuries. Due to its relatively large genome, has great diversity and can use various molecular mechanisms for antimicrobial resistance. For example, outer membrane permeability can contribute to antimicrobial resistance and is determined by lipopolysaccharide (LPS) and porin proteins. Recent findings on the regulatory interaction between peptidoglycan and LPS synthesis provide additional clues against pathogenic . This review focuses on recent advances in antimicrobial agents and inhibitors targeting LPS and porin proteins. In addition, we explore current and emerging treatment strategies for MDR , including phages, vaccines, nanoparticles, and their combinatorial therapies. Novel strategies and their corresponding therapeutic agents are urgently needed for combating MDR pathogens.
PubMed: 38391505
DOI: 10.3390/antibiotics13020119 -
EJNMMI Radiopharmacy and Chemistry Jun 2024Infection remains a major cause of morbidity and mortality, regardless of advances in antimicrobial therapy and improved knowledge of microorganisms. With the major... (Review)
Review
BACKGROUND
Infection remains a major cause of morbidity and mortality, regardless of advances in antimicrobial therapy and improved knowledge of microorganisms. With the major global threat posed by antimicrobial resistance, fast and accurate diagnosis of infections, and the reliable identification of intractable infection, are becoming more crucial for effective treatment and the application of antibiotic stewardship. Molecular imaging with the use of nuclear medicine allows early detection and localisation of infection and inflammatory processes, as well as accurate monitoring of treatment response. There has been a continuous search for more specific radiopharmaceuticals to be utilised for infection imaging. This review summarises the most prominent discoveries in specifically bacterial infection imaging agents over the last five years, since 2019.
MAIN BODY
Some promising new radiopharmaceuticals evaluated in patient studies are reported here, including radiolabelled bacterial siderophores like [Ga]Ga-DFO-B, radiolabelled antimicrobial peptide/peptide fragments like [Ga]Ga-NOTA-UBI29-41, and agents that target bacterial synthesis pathways (folic acid and peptidoglycan) like [C]para-aminobenzoic acid and D-methyl-[C]-methionine, with clinical trials underway for [F]fluorodeoxy-sorbitol, as well as for C- and F-labelled trimethoprim.
CONCLUSION
It is evident that a great deal of effort has gone into the development of new radiopharmaceuticals for infection imaging over the last few years, with remarkable progress in preclinical investigations. However, translation to clinical trials, and eventually clinical Nuclear Medicine practice, is apparently slow. It is the authors' opinion that a more structured and harmonised preclinical setting and well-designed clinical investigations are the key to reliably evaluate the true potential of the newly proposed infection imaging agents.
PubMed: 38896373
DOI: 10.1186/s41181-024-00279-7 -
Current Opinion in Microbiology Jun 2024Members of the order Mycobacteriales are distinguished by a characteristic diderm cell envelope, setting them apart from other Actinobacteria species. In addition to the... (Review)
Review
Members of the order Mycobacteriales are distinguished by a characteristic diderm cell envelope, setting them apart from other Actinobacteria species. In addition to the conventional peptidoglycan cell wall, these organisms feature an extra polysaccharide polymer composed of arabinose and galactose, termed arabinogalactan. The nonreducing ends of arabinose are covalently linked to mycolic acids (MAs), forming the immobile inner leaflet of the highly hydrophobic MA membrane. The contiguous outer leaflet of the MA membrane comprises trehalose mycolates and various lipid species. Similar to all actinobacteria, Mycobacteriales exhibit apical growth, facilitated by a polar localized elongasome complex. A septal cell envelope synthesis machinery, the divisome, builds instead of the cell wall structures during cytokinesis. In recent years, a growing body of knowledge has emerged regarding the cell wall synthesizing complexes of Mycobacteriales., focusing particularly on three model species: Corynebacterium glutamicum, Mycobacterium smegmatis, and Mycobacterium tuberculosis.
Topics: Cell Wall; Mycolic Acids; Galactans; Peptidoglycan; Mycobacterium tuberculosis; Corynebacterium glutamicum; Mycobacterium smegmatis; Arabinose; Bacterial Proteins
PubMed: 38653035
DOI: 10.1016/j.mib.2024.102478 -
Viruses Mar 2024Healthcare faces a major problem with the increased emergence of antimicrobial resistance due to over-prescribing antibiotics. Bacteriophages may provide a solution to... (Review)
Review
Healthcare faces a major problem with the increased emergence of antimicrobial resistance due to over-prescribing antibiotics. Bacteriophages may provide a solution to the treatment of bacterial infections given their specificity. Enzymes such as endolysins, exolysins, endopeptidases, endosialidases, and depolymerases produced by phages interact with bacterial surfaces, cell wall components, and exopolysaccharides, and may even destroy biofilms. Enzymatic cleavage of the host cell envelope components exposes specific receptors required for phage adhesion. Gram-positive bacteria are susceptible to phage infiltration through their peptidoglycan, cell wall teichoic acid (WTA), lipoteichoic acids (LTAs), and flagella. In Gram-negative bacteria, lipopolysaccharides (LPSs), pili, and capsules serve as targets. Defense mechanisms used by bacteria differ and include physical barriers (e.g., capsules) or endogenous mechanisms such as clustered regularly interspaced palindromic repeat (CRISPR)-associated protein (Cas) systems. Phage proteins stimulate immune responses against specific pathogens and improve antibiotic susceptibility. This review discusses the attachment of phages to bacterial cells, the penetration of bacterial cells, the use of phages in the treatment of bacterial infections, and the limitations of phage therapy. The therapeutic potential of phage-derived proteins and the impact that genomically engineered phages may have in the treatment of infections are summarized.
Topics: Humans; Bacteriophages; Bacteria; Bacterial Infections; Gram-Negative Bacteria; Gram-Positive Bacteria
PubMed: 38543843
DOI: 10.3390/v16030478 -
Infection and Immunity Jul 2023It has been widely appreciated that numerous bacterial species express chitinases for the purpose of degrading environmental chitin. However, chitinases and... (Review)
Review
It has been widely appreciated that numerous bacterial species express chitinases for the purpose of degrading environmental chitin. However, chitinases and chitin-binding proteins are also expressed by pathogenic bacterial species during infection even though mammals do not produce chitin. Alternative molecular targets are therefore likely present within the host. Here, we will describe our current understanding of chitinase/chitin-binding proteins as virulence factors that promote bacterial colonization and infection. The targets of these chitinases in the host have been shown to include immune system components, mucins, and surface glycans. Bacterial chitinases have also been shown to interact with other microorganisms, targeting the peptidoglycan or chitin in the bacterial and fungal cell wall, respectively. This review highlights that even though the name "chitinase" implies activity toward chitin, chitinases can have a wide diversity of targets, including ones relevant to host infection. Chitinases may therefore be useful as a target of future anti-infective therapeutics.
Topics: Animals; Humans; Chitinases; Bacteria; Polysaccharides; Chitin; Virulence Factors; Carrier Proteins; Mammals
PubMed: 37255426
DOI: 10.1128/iai.00549-22 -
Current Opinion in Microbiology Aug 2023For bacteria to increase in size, they need to enzymatically expand their cell envelopes, and more concretely their peptidoglycan cell wall. A major task of growth is to... (Review)
Review
For bacteria to increase in size, they need to enzymatically expand their cell envelopes, and more concretely their peptidoglycan cell wall. A major task of growth is to increase intracellular space for the accumulation of macromolecules, notably proteins, RNA, and DNA. Here, we review recent progress in our understanding of how cells coordinate envelope growth with biomass growth, focusing on elongation of rod-like bacteria. We first describe the recent discovery that surface area, but not cell volume, increases in proportion to mass growth. We then discuss how this relation could possibly be implemented mechanistically, reviewing the role of envelope insertion for envelope growth. Since cell-wall expansion requires the well-controlled activity of autolysins, we finally review recent progress in our understanding of autolysin regulation.
Topics: N-Acetylmuramoyl-L-alanine Amidase; Bacterial Proteins; Cell Wall; Cell Membrane; Cell Cycle; Peptidoglycan
PubMed: 37279609
DOI: 10.1016/j.mib.2023.102326 -
Current Biology : CB Aug 2023Antibiotic resistance often confers a fitness cost to the resistant cell and thus raises key questions of how resistance is maintained in the absence of antibiotics and,...
Antibiotic resistance often confers a fitness cost to the resistant cell and thus raises key questions of how resistance is maintained in the absence of antibiotics and, if lost, whether cells are genetically primed for re-evolving resistance. To address these questions, we have examined vancomycin-intermediate Staphylococcus aureus (VISA) strains that arise during vancomycin therapy. VISA strains harbor a broad spectrum of mutations, and they are known to be unstable both in patients and in the laboratory. Here, we show that loss of resistance in VISA strains is correlated with a fitness increase and is attributed to adaptive mutations, leaving the initial VISA-adaptive mutations intact. Importantly, upon a second exposure to vancomycin, such revertants evolve significantly faster to become VISA, and they reach higher resistance levels than vancomycin-naive cells. Further, we find that sub-lethal concentrations of vancomycin stabilize the VISA phenotype, as do the human β-defensin 3 (hBD-3) and the bacteriocin nisin that both, like vancomycin, bind to the peptidoglycan building block, lipid II. Thus, factors binding lipid II may stabilize VISA both in vivo and in vitro, and in case resistance is lost, mutations remain that predispose to resistance development. These findings may explain why VISA infections often are re-occurring and suggest that previous vancomycin adaptation should be considered a risk factor when deciding on antimicrobial chemotherapy.
Topics: Humans; Staphylococcus aureus; Vancomycin; Vancomycin Resistance; Anti-Bacterial Agents; Staphylococcal Infections
PubMed: 37494936
DOI: 10.1016/j.cub.2023.06.082 -
Nature Communications Dec 2023The FtsEX complex regulates, directly or via a protein mediator depending on bacterial genera, peptidoglycan degradation for cell division. In mycobacteria and...
The FtsEX complex regulates, directly or via a protein mediator depending on bacterial genera, peptidoglycan degradation for cell division. In mycobacteria and Gram-positive bacteria, the FtsEX system directly activates peptidoglycan-hydrolases by a mechanism that remains unclear. Here we report our investigation of Mycobacterium tuberculosis FtsEX as a non-canonical regulator with high basal ATPase activity. The cryo-EM structures of the FtsEX system alone and in complex with RipC, as well as the ATP-activated state, unveil detailed information on the signal transduction mechanism, leading to the activation of RipC. Our findings indicate that RipC is recognized through a "Match and Fit" mechanism, resulting in an asymmetric rearrangement of the extracellular domains of FtsX and a unique inclined binding mode of RipC. This study provides insights into the molecular mechanisms of FtsEX and RipC regulation in the context of a critical human pathogen, guiding the design of drugs targeting peptidoglycan remodeling.
Topics: Humans; Cell Cycle Proteins; Mycobacterium tuberculosis; Hydrolases; Bacterial Proteins; Peptidoglycan; Cell Division
PubMed: 38044344
DOI: 10.1038/s41467-023-43770-6