Structural mechanism for modulation of functional amyloid and biofilm formation by Staphylococcal Bap protein switch

Ma, Junfeng; Cheng, Xueqing; Xu, Zhonghe; Zhang, Yikan; Valle, Jaione; Fan, Shilong; Zuo, Xiaobing; Lasa, Íñigo

doi:10.15252/embj.2020107500

Cited by 26 publications

(16 citation statements)

References 49 publications

(68 reference statements)

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“…The surface-exposed polyproline helix of CupB6 is part of the adhesion domain, and is believed to mediate a range of protein-protein interactions (Rasheed et al, 2016). In S. aureus , Target ID 37 or ‘biofilm-associated surface protein’, mediates intercellular adhesion and biofilm formation, with the N-terminal lobe of the protein identified to have a significant role (Ma et al, 2021). A filtered list of 2035 AMPs known to have both anti-Gram positive and anti-Gram negative activity (from B-AMP v1.0) (Suppl File 11) , were docked with the identified active site regions of the biofilm targets using AutoDock v4.2.…”

Section: Resultsmentioning

confidence: 99%

‘Targeting’ the Search: An Upgraded Structural and Functional Repository of Antimicrobial Peptides for Biofilm Studies (B-AMP v2.0) with a Focus on Biofilm Protein Targets

Ravichandran

Avatapalli

Narasimhan

et al. 2022

Preprint

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Bacterial biofilms, often as multispecies communities, are recalcitrant to conventional antibiotics, making the treatment of biofilm infections a challenge. There is a push towards developing novel anti-biofilm approaches, such as antimicrobial peptides (AMPs), with activity against specific biofilm targets. In previous work, we developed Biofilm-AMP, a structural and functional repository of AMPs for biofilm studies (B-AMP v1.0) with more than 5000 structural models of AMPs and a vast library of AMP annotations to existing biofilm literature. In this study, we present an upgraded version of B-AMP, with a focus on existing and novel bacterial biofilm targets. B-AMP v2.0 hosts a curated collection of 2502 biofilm protein targets across 473 bacterial species, with structural protein models and functional annotations from PDB, UniProt, and PubMed databases. The biofilm targets can be searched for using the name of the source organism, and function and type of protein, and results include designated Target IDs (unique to B-AMP v2.0), UniProt IDs, 3D predicted protein structures, PDBQT files, pre-defined protein function, and relevant scientific literature. To present an example of the combined applicability of both, the AMP and biofilm target libraries in the repository, we present two case studies. In the first case study, we expand an in silico pipeline to evaluate AMPs against a single biofilm target in the multidrug resistant, bacterial pathogen Corynebacterium striatum, using 3D protein-peptide docking models from previous work and Molecular Dynamics simulations (~1.18 microseconds). In the second case study, we build an in silico pipeline to identify candidate AMPs (using AMPs with both anti-Gram positive and anti-Gram negative activity) against two biofilm targets with a common functional classification in Pseudomonas aeruginosa and Staphylococcus aureus, widely-encountered bacterial co-pathogens. With its enhanced structural and functional capabilities, B-AMP v2.0 serves as a comprehensive resource for AMP investigations related to biofilm studies. B-AMP v2.0 is freely available at https://b-amp.karishmakaushiklab.com and will be regularly updated with structural models of AMPs and biofilm targets, as well as 3D protein-peptide interaction models for key biofilm-forming pathogens.

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Section: Resultsmentioning

confidence: 99%

‘Targeting’ the Search: An Upgraded Structural and Functional Repository of Antimicrobial Peptides for Biofilm Studies (B-AMP v2.0) with a Focus on Biofilm Protein Targets

Ravichandran

Avatapalli

Narasimhan

et al. 2022

Preprint

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“…DEv-Ig domains are common among bacterial adhesins, and while it remains possible that these domains in Esp have host targets, we instead identified a function that required unfolding of these domains into amyloid-like structures that strengthen biofilms. The structurally related proteins Bap and Antigen I/II also have DEv-Ig folds and form amyloid-like structures that localize to biofilms (47,(54)(55)(56), indicating that DEv-Ig folds can have biofilm-related functions in addition to adhesive ones. We found that Esp743 strengthened biofilms, as did Esp452 and the shorter EspDDDK fragment, suggesting that this capacity is resident at the very N-terminal portion of Esp.…”

Section: Discussionmentioning

confidence: 99%

Strengthening of enterococcal biofilms by Esp

Spiegelman

Bahn-Suh

Montaño

et al. 2022

Preprint

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Multidrug-resistant (MDR) Enterococcus faecalis are major causes of hospital-acquired infections. Numerous clinical strains harbor a large pathogenicity island that encodes enterococcal surface protein (Esp), which is suggested to promote biofilm production and virulence, but this remains controversial. To resolve this issue, we characterized the Esp N-terminal region, the portion implicated in biofilm production. Small angle X-ray scattering indicated that the N-terminal region had a globular head, which consisted of two DEv-Ig domains as visualized by X-ray crystallography, followed by an extended tail. The N-terminal region was not required for biofilm production but instead significantly strengthened biofilms against mechanical or degradative disruption, greatly increasing retention of Enterococcus within biofilms. Biofilm strengthening required low pH, which resulted in Esp unfolding, aggregating, and forming amyloid-like structures. The pH threshold for biofilm strengthening depended on protein stability. A truncated fragment of the first DEv-Ig domain, plausibly generated by a host protease, was the least stable and sufficient to strengthen biofilms at pH ≤ 5.0, while the entire N-terminal region and intact Esp on the enterococcal surface was more stable and required a pH ≤ 4.3. These results suggested a virulence role of Esp in strengthening enterococcal biofilms in acidic abiotic or host environments.

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“…The ability of pathogenic bacteria to form biofilms is one of the key issues that must be addressed to maintain public health. It is known that amyloidogenic proteins promote the primary stage of cell adhesion to the substrate, cell aggregation, and are necessary for the formation of the biofilm matrix [49][50][51][52]. There are also facts confirming the possibility of preventing the formation of biofilms using amyloidogenic antimicrobial peptides.…”

Section: Introductionmentioning

confidence: 99%

Amyloidogenic Peptides: New Class of Antimicrobial Peptides with the Novel Mechanism of Activity

Galzitskaya

Kurpe

Panfilov

et al. 2022

IJMS

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Antibiotic-resistant bacteria are recognized as one of the leading causes of death in the world. We proposed and successfully tested peptides with a new mechanism of antimicrobial action “protein silencing” based on directed co-aggregation. The amyloidogenic antimicrobial peptide (AAMP) interacts with the target protein of model or pathogenic bacteria and forms aggregates, thereby knocking out the protein from its working condition. In this review, we consider antimicrobial effects of the designed peptides on two model organisms, E. coli and T. thermophilus, and two pathogenic organisms, P. aeruginosa and S. aureus. We compare the amino acid composition of proteomes and especially S1 ribosomal proteins. Since this protein is inherent only in bacterial cells, it is a good target for studying the process of co-aggregation. This review presents a bioinformatics analysis of these proteins. We sum up all the peptides predicted as amyloidogenic by several programs and synthesized by us. For the four organisms we studied, we show how amyloidogenicity correlates with antibacterial properties. Let us especially dwell on peptides that have demonstrated themselves as AMPs for two pathogenic organisms that cause dangerous hospital infections, and in which the minimal inhibitory concentration (MIC) turned out to be comparable to the MIC of gentamicin sulfate. All this makes our study encouraging for the further development of AAMP. The hybrid peptides may thus provide a starting point for the antibacterial application of amyloidogenic peptides.

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Structural mechanism for modulation of functional amyloid and biofilm formation by Staphylococcal Bap protein switch

Cited by 26 publications

References 49 publications

‘Targeting’ the Search: An Upgraded Structural and Functional Repository of Antimicrobial Peptides for Biofilm Studies (B-AMP v2.0) with a Focus on Biofilm Protein Targets

‘Targeting’ the Search: An Upgraded Structural and Functional Repository of Antimicrobial Peptides for Biofilm Studies (B-AMP v2.0) with a Focus on Biofilm Protein Targets

Strengthening of enterococcal biofilms by Esp

Amyloidogenic Peptides: New Class of Antimicrobial Peptides with the Novel Mechanism of Activity

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