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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 -
Membrane translocation process revealed by in situ structures of type II secretion system secretins.Nature Communications Jul 2023The GspD secretin is the outer membrane channel of the bacterial type II secretion system (T2SS) which secrets diverse toxins that cause severe diseases such as diarrhea...
The GspD secretin is the outer membrane channel of the bacterial type II secretion system (T2SS) which secrets diverse toxins that cause severe diseases such as diarrhea and cholera. GspD needs to translocate from the inner to the outer membrane to exert its function, and this process is an essential step for T2SS to assemble. Here, we investigate two types of secretins discovered so far in Escherichia coli, GspD, and GspD. By electron cryotomography subtomogram averaging, we determine in situ structures of key intermediate states of GspD and GspD in the translocation process, with resolution ranging from 9 Å to 19 Å. In our results, GspD and GspD present entirely different membrane interaction patterns and ways of transitioning the peptidoglycan layer. From this, we hypothesize two distinct models for the membrane translocation of GspD and GspD, providing a comprehensive perspective on the inner to outer membrane biogenesis of T2SS secretins.
Topics: Type II Secretion Systems; Secretin; Escherichia coli; Escherichia coli Proteins; Bacterial Proteins; Bacterial Outer Membrane Proteins
PubMed: 37419909
DOI: 10.1038/s41467-023-39583-2 -
Current Biology : CB Sep 2023Pattern-recognition receptor (PRR)-triggered immunity (PTI) wards off a wide range of pathogenic microbes, playing a pivotal role in angiosperms. The model liverwort...
Pattern-recognition receptor (PRR)-triggered immunity (PTI) wards off a wide range of pathogenic microbes, playing a pivotal role in angiosperms. The model liverwort Marchantia polymorpha triggers defense-related gene expression upon sensing components of bacterial and fungal extracts, suggesting the existence of PTI in this plant model. However, the molecular components of the putative PTI in M. polymorpha and the significance of PTI in bryophytes have not yet been described. We here show that M. polymorpha has four lysin motif (LysM)-domain-containing receptor homologs, two of which, LysM-receptor-like kinase (LYK) MpLYK1 and LYK-related (LYR) MpLYR, are responsible for sensing chitin and peptidoglycan fragments, triggering a series of characteristic immune responses. Comprehensive phosphoproteomic analysis of M. polymorpha in response to chitin treatment identified regulatory proteins that potentially shape LysM-mediated PTI. The identified proteins included homologs of well-described PTI components in angiosperms as well as proteins whose roles in PTI are not yet determined, including the blue-light receptor phototropin MpPHOT. We revealed that MpPHOT is required for negative feedback of defense-related gene expression during PTI. Taken together, this study outlines the basic framework of LysM-mediated PTI in M. polymorpha and highlights conserved elements and new aspects of pattern-triggered immunity in land plants.
Topics: Chitin; Embryophyta; Innate Immunity Recognition; Magnoliopsida; Marchantia; Lysine
PubMed: 37619565
DOI: 10.1016/j.cub.2023.07.068 -
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 -
ELife Jul 2023The bloodstream represents a hostile environment that bacteria must overcome to cause bacteraemia. To understand how the major human pathogen manages this we have...
The bloodstream represents a hostile environment that bacteria must overcome to cause bacteraemia. To understand how the major human pathogen manages this we have utilised a functional genomics approach to identify a number of new loci that affect the ability of the bacteria to survive exposure to serum, the critical first step in the development of bacteraemia. The expression of one of these genes, was found to be induced upon exposure to serum, and we show that it is involved in the elaboration of a critical virulence factor, the wall teichoic acids (WTA), within the cell envelope. The activity of the TcaA protein alters the sensitivity of the bacteria to cell wall attacking agents, including antimicrobial peptides, human defence fatty acids, and several antibiotics. This protein also affects the autolytic activity and lysostaphin sensitivity of the bacteria, suggesting that in addition to changing WTA abundance in the cell envelope, it also plays a role in peptidoglycan crosslinking. With TcaA rendering the bacteria more susceptible to serum killing, while simultaneously increasing the abundance of WTA in the cell envelope, it was unclear what effect this protein may have during infection. To explore this, we examined human data and performed murine experimental infections. Collectively, our data suggests that whilst mutations in are selected for during bacteraemia, this protein positively contributes to the virulence of through its involvement in altering the cell wall architecture of the bacteria, a process that appears to play a key role in the development of bacteraemia.
Topics: Animals; Humans; Mice; Staphylococcal Infections; Bacteremia; Staphylococcus aureus; Cell Wall; Anti-Bacterial Agents; Teichoic Acids
PubMed: 37401629
DOI: 10.7554/eLife.87026 -
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 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