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Nature Jun 2017Urinary tract infections (UTIs) caused by uropathogenic Escherichia coli (UPEC) affect 150 million people annually. Despite effective antibiotic therapy, 30-50% of...
Urinary tract infections (UTIs) caused by uropathogenic Escherichia coli (UPEC) affect 150 million people annually. Despite effective antibiotic therapy, 30-50% of patients experience recurrent UTIs. In addition, the growing prevalence of UPEC that are resistant to last-line antibiotic treatments, and more recently to carbapenems and colistin, make UTI a prime example of the antibiotic-resistance crisis and emphasize the need for new approaches to treat and prevent bacterial infections. UPEC strains establish reservoirs in the gut from which they are shed in the faeces, and can colonize the periurethral area or vagina and subsequently ascend through the urethra to the urinary tract, where they cause UTIs. UPEC isolates encode up to 16 distinct chaperone-usher pathway pili, and each pilus type may enable colonization of a habitat in the host or environment. For example, the type 1 pilus adhesin FimH binds mannose on the bladder surface, and mediates colonization of the bladder. However, little is known about the mechanisms underlying UPEC persistence in the gut. Here, using a mouse model, we show that F17-like and type 1 pili promote intestinal colonization and show distinct binding to epithelial cells distributed along colonic crypts. Phylogenomic and structural analyses reveal that F17-like pili are closely related to pilus types carried by intestinal pathogens, but are restricted to extra-intestinal pathogenic E. coli. Moreover, we show that targeting FimH with M4284, a high-affinity inhibitory mannoside, reduces intestinal colonization of genetically diverse UPEC isolates, while simultaneously treating UTI, without notably disrupting the structural configuration of the gut microbiota. By selectively depleting intestinal UPEC reservoirs, mannosides could markedly reduce the rate of UTIs and recurrent UTIs.
Topics: Adhesins, Escherichia coli; Amino Acid Sequence; Animals; Epithelial Cells; Feces; Female; Fimbriae Proteins; Fimbriae, Bacterial; Humans; Intestines; Mannosides; Mice; Models, Molecular; Phthalic Acids; Urinary Bladder; Urinary Tract Infections; Uropathogenic Escherichia coli
PubMed: 28614296
DOI: 10.1038/nature22972 -
Frontiers in Cellular and Infection... 2023The pilus is an extracellular structural part that can be detected in some () isolates (type I pili are found in approximately 30% of strains, while type II pili are... (Review)
Review
The pilus is an extracellular structural part that can be detected in some () isolates (type I pili are found in approximately 30% of strains, while type II pili are found in approximately 20%). It is anchored to the cell wall by LPXTG-like motifs on the peptidoglycan. Two kinds of pili have been discovered, namely, pilus-1 and pilus-2. The former is encoded by pilus islet 1 (PI-1) and is a polymer formed by the protein subunits RrgA, RrgB and RrgC. The latter is encoded by pilus islet 2 (PI-2) and is a polymer composed mainly of the structural protein PitB. Although pili are not necessary for the survival of , they serve as the structural basis and as virulence factors that mediate the adhesion of bacteria to host cells and play a direct role in promoting the adhesion, colonization and pathogenesis of . In addition, as candidate antigens for protein vaccines, pili have promising potential for use in vaccines with combined immunization strategies. Given the current understanding of the pili of regarding the genes, proteins, structure, biological function and epidemiological relationship with serotypes, combined with the immunoprotective efficacy of pilins as protein candidates for vaccines, we here systematically describe the research status and prospects of pili and provide new ideas for subsequent vaccine research and development.
Topics: Bacterial Proteins; Streptococcus pneumoniae; Fimbriae, Bacterial; Fimbriae Proteins; Vaccines; Polymers
PubMed: 37799336
DOI: 10.3389/fcimb.2023.1270848 -
Microbiology Spectrum Mar 2019Type IV pilus (T4P)-like systems have been identified in almost every major phylum of prokaryotic life. They include the type IVa pilus (T4aP), type II secretion system... (Review)
Review
Type IV pilus (T4P)-like systems have been identified in almost every major phylum of prokaryotic life. They include the type IVa pilus (T4aP), type II secretion system (T2SS), type IVb pilus (T4bP), Tad/Flp pilus, Com pilus, and archaeal flagellum (archaellum). These systems are used for adhesion, natural competence, phage adsorption, folded-protein secretion, surface sensing, swimming motility, and twitching motility. The T4aP allows for all of these functions except swimming and is therefore a good model system for understanding T4P-like systems. Recent structural analyses have revolutionized our understanding of how the T4aP machinery assembles and functions. Here we review the structure and function of the T4aP.
Topics: Fimbriae Proteins; Fimbriae, Bacterial; Flagella; Protein Transport; Type II Secretion Systems
PubMed: 30825300
DOI: 10.1128/microbiolspec.PSIB-0006-2018 -
Microbial Biotechnology Nov 2018The reduction of iron oxide minerals and uranium in model metal reducers in the genus Geobacter is mediated by conductive pili composed primarily of a structurally... (Review)
Review
The reduction of iron oxide minerals and uranium in model metal reducers in the genus Geobacter is mediated by conductive pili composed primarily of a structurally divergent pilin peptide that is otherwise recognized, processed and assembled in the inner membrane by a conserved Type IVa pilus apparatus. Electronic coupling among the peptides is promoted upon assembly, allowing the discharge of respiratory electrons at rates that greatly exceed the rates of cellular respiration. Harnessing the unique properties of these conductive appendages and their peptide building blocks in metal bioremediation will require understanding of how the pilins assemble to form a protein nanowire with specialized sites for metal immobilization. Also important are insights into how cells assemble the pili to make an electroactive matrix and grow on electrodes as biofilms that harvest electrical currents from the oxidation of waste organic substrates. Genetic engineering shows promise to modulate the properties of the peptide building blocks, protein nanowires and current-harvesting biofilms for various applications. This minireview discusses what is known about the pilus material properties and reactions they catalyse and how this information can be harnessed in nanotechnology, bioremediation and bioenergy applications.
Topics: Bacterial Proteins; Biofilms; Biotechnology; Electrodes; Fimbriae, Bacterial; Geobacter; Nanowires; Oxidation-Reduction
PubMed: 29806247
DOI: 10.1111/1751-7915.13280 -
International Journal of Molecular... Jul 2017One of the more conspicuous structural features that punctuate the outer cell surface of certain bacterial Gram-positive genera and species is the sortase-dependent... (Review)
Review
One of the more conspicuous structural features that punctuate the outer cell surface of certain bacterial Gram-positive genera and species is the sortase-dependent pilus. As these adhesive and variable-length protrusions jut outward from the cell, they provide a physically expedient and useful means for the initial contact between a bacterium and its ecological milieu. The sortase-dependent pilus displays an elongated macromolecular architecture consisting of two to three types of monomeric protein subunits (pilins), each with their own specific function and location, and that are joined together covalently by the transpeptidyl activity of a pilus-specific C-type sortase enzyme. Sortase-dependent pili were first detected among the Gram-positive pathogens and subsequently categorized as an essential virulence factor for host colonization and tissue invasion by these harmful bacteria. However, the sortase-dependent pilus was rebranded as also a niche-adaptation factor after it was revealed that "friendly" Gram-positive commensals exhibit the same kind of pilus structures, which includes two contrasting gut-adapted species from the genus, allochthonous and autochthonous . This review will highlight and discuss what has been learned from the latest research carried out and published on these lactobacillar pilus types.
Topics: Aminoacyltransferases; Bacterial Proteins; Cysteine Endopeptidases; Fimbriae, Bacterial; Lactobacillus; Models, Molecular
PubMed: 28718795
DOI: 10.3390/ijms18071551 -
Structure (London, England : 1993) Dec 2021Type IV pili (T4P) are distinctive dynamic filaments at the surface of many bacteria that can rapidly extend and retract and withstand strong forces. T4P are important...
Type IV pili (T4P) are distinctive dynamic filaments at the surface of many bacteria that can rapidly extend and retract and withstand strong forces. T4P are important virulence factors in many human pathogens, including Enterohemorrhagic Escherichia coli (EHEC). The structure of the EHEC T4P has been determined by integrating nuclear magnetic resonance (NMR) and cryo-electron microscopy data. To better understand pilus assembly, stability, and function, we performed a total of 108 ms all-atom molecular dynamics simulations of wild-type and mutant T4P. Extensive characterization of the conformational landscape of T4P in different conditions of temperature, pH, and ionic strength is complemented with targeted mutagenesis and biochemical analyses. Our simulations and NMR experiments reveal a conserved set of residues defining a calcium-binding site at the interface between three pilin subunits. Calcium binding enhances T4P stability ex vivo and in vitro, supporting the role of this binding site as a potential pocket for drug design.
Topics: Binding Sites; Cryoelectron Microscopy; Enterohemorrhagic Escherichia coli; Fimbriae Proteins; Fimbriae, Bacterial; Molecular Dynamics Simulation
PubMed: 34520738
DOI: 10.1016/j.str.2021.07.008 -
Nature Reviews. Microbiology May 2017Pili are crucial virulence factors for many Gram-negative pathogens. These surface structures provide bacteria with a link to their external environments by enabling... (Review)
Review
Pili are crucial virulence factors for many Gram-negative pathogens. These surface structures provide bacteria with a link to their external environments by enabling them to interact with, and attach to, host cells, other surfaces or each other, or by providing a conduit for secretion. Recent high-resolution structures of pilus filaments and the machineries that produce them, namely chaperone-usher pili, type IV pili, conjugative type IV secretion pili and type V pili, are beginning to explain some of the intriguing biological properties that pili exhibit, such as the ability of chaperone-usher pili and type IV pili to stretch in response to external forces. By contrast, conjugative pili provide a conduit for the exchange of genetic information, and recent high-resolution structures have revealed an integral association between the pilin subunit and a phospholipid molecule, which may facilitate DNA transport. In addition, progress in the area of cryo-electron tomography has provided a glimpse of the overall architecture of the type IV pilus machinery. In this Review, we examine recent advances in our structural understanding of various Gram-negative pilus systems and discuss their functional implications.
Topics: Bacterial Adhesion; Conjugation, Genetic; Fimbriae Proteins; Fimbriae, Bacterial; Gram-Negative Bacteria; Virulence Factors
PubMed: 28496159
DOI: 10.1038/nrmicro.2017.40 -
EcoSal Plus Mar 2019The chaperone-usher (CU) pathway is a conserved secretion system dedicated to the assembly of a superfamily of virulence-associated surface structures by a wide range of... (Review)
Review
The chaperone-usher (CU) pathway is a conserved secretion system dedicated to the assembly of a superfamily of virulence-associated surface structures by a wide range of Gram-negative bacteria. Pilus biogenesis by the CU pathway requires two specialized assembly components: a dedicated periplasmic chaperone and an integral outer membrane assembly and secretion platform termed the usher. The CU pathway assembles a variety of surface fibers, ranging from thin, flexible filaments to rigid, rod-like organelles. Pili typically act as adhesins and function as virulence factors that mediate contact with host cells and colonization of host tissues. Pilus-mediated adhesion is critical for early stages of infection, allowing bacteria to establish a foothold within the host. Pili are also involved in modulation of host cell signaling pathways, bacterial invasion into host cells, and biofilm formation. Pili are critical for initiating and sustaining infection and thus represent attractive targets for the development of antivirulence therapeutics. Such therapeutics offer a promising alternative to broad-spectrum antibiotics and provide a means to combat antibiotic resistance and treat infection while preserving the beneficial microbiota. A number of strategies have been taken to develop antipilus therapeutics, including vaccines against pilus proteins, competitive inhibitors of pilus-mediated adhesion, and small molecules that disrupt pilus biogenesis. Here we provide an overview of the function and assembly of CU pili and describe current efforts aimed at interfering with these critical virulence structures.
Topics: Adhesins, Bacterial; Bacterial Secretion Systems; Clinical Trials as Topic; Escherichia coli Proteins; Fimbriae Proteins; Fimbriae, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Models, Molecular; Molecular Chaperones; Uropathogenic Escherichia coli; Virulence
PubMed: 30873935
DOI: 10.1128/ecosalplus.ESP-0033-2018 -
Molecular Microbiology Feb 2018Archaea are ubiquitously present in nature and colonize environments with broadly varying growth conditions. Several surface appendages support their colonization of new... (Review)
Review
Archaea are ubiquitously present in nature and colonize environments with broadly varying growth conditions. Several surface appendages support their colonization of new habitats. A hallmark of archaea seems to be the high abundance of type IV pili (T4P). However, some unique non T4 filaments are present in a number of archaeal species. Archaeal surface structures can mediate different processes such as cellular surface adhesion, DNA exchange, motility and biofilm formation and represent an initial attachment site for infecting viruses. In addition to the functionally characterized archaeal T4P, archaeal genomes encode a large number of T4P components that might form yet undiscovered surface structures with novel functions. In this review, we summarize recent advancement in structural and functional characterizations of known archaeal surface structures and highlight the diverse processes in which they play a role.
Topics: Archaea; Bacterial Adhesion; Biofilms; Fimbriae, Bacterial; Membrane Proteins; Pili, Sex
PubMed: 29194812
DOI: 10.1111/mmi.13889 -
Microbiology and Molecular Biology... Sep 2022Type IV pili (T4P) are retractable multifunctional nanofibers present on the surface of numerous bacterial and archaeal species. Their importance to microbiology is... (Review)
Review
Type IV pili (T4P) are retractable multifunctional nanofibers present on the surface of numerous bacterial and archaeal species. Their importance to microbiology is difficult to overstate. The scientific journey leading to our current understanding of T4P structure and function has included many innovative research milestones. Although multiple T4P reviews over the years have emphasized recent advances, we find that current reports often omit many of the landmark discoveries in this field. Here, we attempt to highlight chronologically the most important work on T4P, from the discovery of pili to the application of sophisticated contemporary methods, which has brought us to our current state of knowledge. As there remains much to learn about the complex machine that assembles and retracts T4P, we hope that this review will increase the interest of current researchers and inspire innovative progress.
Topics: Archaea; Bacteria; Fimbriae, Bacterial
PubMed: 35612326
DOI: 10.1128/mmbr.00076-22