scholarly journals New N-(oxazolylmethyl)-thiazolidinedione Active against Candida albicans Biofilm: Potential Als Proteins Inhibitors

Molecules ◽  
2018 ◽  
Vol 23 (10) ◽  
pp. 2522 ◽  
Author(s):  
Gabriel Marc ◽  
Cătălin Araniciu ◽  
Smaranda Oniga ◽  
Laurian Vlase ◽  
Adrian Pîrnău ◽  
...  
Keyword(s):  
Biofilm Formation ◽  
Infection Prevention ◽  
Public Health Problem ◽  
Opportunistic Pathogen ◽  
Surface Proteins ◽  
Form Complex ◽  
New Approach ◽  
New Class ◽  
New Compounds

C. albicans is the most frequently occurring fungal pathogen, and is becoming an increasing public health problem, especially in the context of increased microbial resistance. This opportunistic pathogen is characterized by a versatility explained mainly by its ability to form complex biofilm structures that lead to enhanced virulence and antibiotic resistance. In this context, a review of the known C. albicans biofilm formation inhibitors were performed and a new N-(oxazolylmethyl)-thiazolidinedione scaffold was constructed. 16 new compounds were synthesized and characterized in order to confirm their proposed structures. A general antimicrobial screening against Gram-positive and Gram-negative bacteria, as well as fungi, was performed and revealed that the compounds do not have direct antimicrobial activity. The anti-biofilm activity evaluation confirmed the compounds act as selective inhibitors of C. albicans biofilm formation. In an effort to substantiate this biologic profile, we used in silico investigations which suggest that the compounds could act by binding, and thus obstructing the functions of, the C. albicans Als surface proteins, especially Als1, Als3, Als5 and Als6. Considering the well documented role of Als1 and Als3 in biofilm formation, our new class of compounds that target these proteins could represent a new approach in C. albicans infection prevention and management.

scholarly journals Thiazole Analogues of the Marine Alkaloid Nortopsentin as Inhibitors of Bacterial Biofilm Formation

Molecules ◽  
2020 ◽  
Vol 26 (1) ◽  
pp. 81
Author(s):  
Anna Carbone ◽  
Stella Cascioferro ◽  
Barbara Parrino ◽  
Daniela Carbone ◽  
Camilla Pecoraro ◽  
...  
Keyword(s):  
Biofilm Formation ◽  
Bacterial Biofilm ◽  
Thiazole Derivatives ◽  
Gram Positive ◽  
Lead Compounds ◽  
New Class ◽  
Marked Selectivity ◽  
Global Threat ◽  
New Compounds ◽  
Reference Strains

Anti-virulence strategy is currently considered a promising approach to overcome the global threat of the antibiotic resistance. Among different bacterial virulence factors, the biofilm formation is recognized as one of the most relevant. Considering the high and growing percentage of multi-drug resistant infections that are biofilm-mediated, new therapeutic agents capable of counteracting the formation of biofilms are urgently required. In this scenario, a new series of 18 thiazole derivatives was efficiently synthesized and evaluated for its ability to inhibit biofilm formation against the Gram-positive bacterial reference strains Staphylococcus aureus ATCC 25923 and S. aureus ATCC 6538 and the Gram-negative strain Pseudomonas aeruginosa ATCC 15442. Most of the new compounds showed a marked selectivity against the Gram-positive strains. Remarkably, five compounds exhibited BIC50 values against S. aureus ATCC 25923 ranging from 1.0 to 9.1 µM. The new compounds, affecting the biofilm formation without any interference on microbial growth, can be considered promising lead compounds for the development of a new class of anti-virulence agents.

scholarly journals PmtA Regulates Pyocyanin Expression and Biofilm Formation in Pseudomonas aeruginosa

2021 ◽  
Vol 12 ◽  
Author(s):  
Amy V. Thees ◽  
Kathryn M. Pietrosimone ◽  
Clare K. Melchiorre ◽  
Jeremiah N. Marden ◽  
Joerg Graf ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Pseudomonas Aeruginosa ◽  
Metal Binding ◽  
Biofilm Formation ◽  
Binding Capacity ◽  
Opportunistic Pathogen ◽  
Small Molecular Weight ◽  
Heavy Metal Binding ◽  
The Impact

The opportunistic pathogen Pseudomonas aeruginosa expresses a small molecular weight, cysteine-rich protein (PmtA), identified as a metallothionein (MT) protein family member. The MT family proteins have been well-characterized in eukaryotes as essential for zinc and copper homeostasis, protection against oxidative stress, and the ability to modify a variety of immune activities. Bacterial MTs share sequence homology, antioxidant chemistry, and heavy metal-binding capacity with eukaryotic MTs, however, the impact of bacterial MTs on virulence and infection have not been well-studied. In the present study, we investigated the role of PmtA in P. aeruginosa PAO1 using a PmtA-deficient strain (ΔpmtA). Here we demonstrated the virulence factor, pyocyanin, relies on the expression of PmtA. We showed that PmtA may be protective against oxidative stress, as an alternative antioxidant, glutathione, can rescue pyocyanin expression. Furthermore, the expression of phzM, which encodes a pyocyanin precursor enzyme, was decreased in the ΔpmtA mutant during early stationary phase. Upregulated pmtA expression was previously detected in confluent biofilms, which are essential for chronic infection, and we observed that the ΔpmtA mutant was disrupted for biofilm formation. As biofilms also modulate antibiotic susceptibility, we examined the ΔpmtA mutant susceptibility to antibiotics and found that the ΔpmtA mutant is more susceptible to cefepime and ciprofloxacin than the wild-type strain. Finally, we observed that the deletion of pmtA results in decreased virulence in a waxworm model. Taken together, our results support the conclusion that PmtA is necessary for the full virulence of P. aeruginosa and may represent a potential target for therapeutic intervention.

scholarly journals The role of an innovative disinfection system based on silver and hydrogen peroxide in infection prevention

2021 ◽  
Vol 343 ◽  
pp. 10003
Author(s):  
Martin Heinisch ◽  
Laura Heinisch ◽  
Dan Miricescu
Keyword(s):  
Hydrogen Peroxide ◽  
Genetic Information ◽  
Infection Prevention ◽  
Surface Proteins ◽  
Transmission Route ◽  
The Novel ◽  
Disinfection Methods ◽  
Virus Integration ◽  
Virus Spreading

Due to the current pandemic situation caused by SARS-CoV-2 the need of effective precautionary methods is increasing. Besides the transmission of this virus by aerosols induced to air, it is assumed that the transmission route of SARS-CoV-2 is mainly by contaminated surfaces. It has been demonstrated that viruses can contaminate dry surfaces and can be further transmitted to the host even after extended time. The amount of disinfection and hygiene systems has increased drastically over the recent year. Although, the conventional disinfection method via spraying and wiping is labour intensive and efficacy is dependent on the application. Aim of this study was to improve conventional disinfection methods. This new disinfection system based on hydrogen peroxide and silver nanoparticles displays a quick and effective alternative. The composition which was proposed in this study shows unique features in terms of application, health risk and effectivity. The novel application by vaporization helps to disinfect the environment and even the air to reduce virus spreading. New disinfection formulation shows efficacy on the surface proteins and genetic information of the virus. Integration of the effective disinfection method shown in this study in the current precaution measurements will help to reduce the spread of SARS-CoV-2.

scholarly journals Function of BriC Peptide in the Pneumococcal Competence and Virulence Portfolio

2018 ◽  
Author(s):  
Surya D. Aggarwal ◽  
Rory Eutsey ◽  
Jacob West-Roberts ◽  
Arnau Domenech ◽  
Wenjie Xu ◽  
...  
Keyword(s):  
Murine Model ◽  
Biofilm Formation ◽  
Opportunistic Pathogen ◽  
Nasopharyngeal Colonization ◽  
Point Of Entry ◽  
Abiotic Surfaces ◽  
Biofilm Development

AbstractStreptococcus pneumoniae (pneumococcus) is an opportunistic pathogen that causes otitis media, sinusitis, pneumonia, meningitis and sepsis. The progression to this pathogenic lifestyle is preceded by asymptomatic colonization of the nasopharynx. This colonization is associated with biofilm formation; the competence pathway influences the structure and stability of biofilms. However, the molecules that link the competence pathway to biofilm formation are unknown. Here, we describe a new competence-induced gene, called briC, and demonstrate that its product promotes biofilm development and stimulates colonization in a murine model. We show that expression of briC is induced by the master regulator of competence, ComE. Whereas briC does not substantially influence early biofilm development on abiotic surfaces, it significantly impacts later stages of biofilm development. Specifically, briC expression leads to increases in biofilm biomass and thickness at 72h. Consistent with the role of biofilms in colonization, briC promotes nasopharyngeal colonization in the murine model. The function of BriC appears to be conserved across pneumococci, as comparative genomics reveal that briC is widespread across isolates. Surprisingly, many isolates, including strains from clinically important PMEN1 and PMEN14 lineages, which are widely associated with colonization, encode a long briC promoter. This long form captures an instance of genomic plasticity and functions as a competence-independent expression enhancer that may serve as a precocious point of entry into this otherwise competence-regulated pathway. Moreover, overexpression of briC by the long promoter fully rescues the comE-deletion induced biofilm defect in vitro, and partially in vivo. These findings indicate that BriC may bypass the influence of competence in biofilm development and that such a pathway may be active in a subset of pneumococcal lineages. In conclusion, BriC is a part of the complex molecular network that connects signaling of the competence pathway to biofilm development and colonization.

scholarly journals Cross-talk between individual phenol-soluble modulins in Staphylococcus aureus biofilm enables rapid and efficient amyloid formation

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Masihuz Zaman ◽  
Maria Andreasen
Keyword(s):  
Staphylococcus Aureus ◽  
Self Assembly ◽  
Biofilm Formation ◽  
Opportunistic Pathogen ◽  
Amyloid Formation ◽  
Secondary Nucleation ◽  
Primary Nucleation ◽  
Functional Amyloids ◽  
High Degree

The infective ability of the opportunistic pathogen Staphylococcus aureus, recognized as the most frequent cause of biofilm-associated infections, is associated with biofilm-mediated resistance to host immune response. Phenol-soluble modulins (PSM) comprise the structural scaffold of S. aureus biofilms through self-assembly into functional amyloids, but the role of individual PSMs during biofilm formation remains poorly understood and the molecular pathways of PSM self-assembly are yet to be identified. Here we demonstrate high degree of cooperation between individual PSMs during functional amyloid formation. PSMα3 initiates the aggregation, forming unstable aggregates capable of seeding other PSMs resulting in stable amyloid structures. Using chemical kinetics we dissect the molecular mechanism of aggregation of individual PSMs showing that PSMα1, PSMα3 and PSMβ1 display secondary nucleation whereas PSMβ2 aggregates through primary nucleation and elongation. Our findings suggest that various PSMs have evolved to ensure fast and efficient biofilm formation through cooperation between individual peptides.

scholarly journals The Terminal A Domain of the Fibrillar Accumulation-Associated Protein (Aap) of Staphylococcus epidermidis Mediates Adhesion to Human Corneocytes

2009 ◽  
Vol 191 (22) ◽  
pp. 7007-7016 ◽  
Author(s):  
Robin L. Macintosh ◽  
Jane L. Brittan ◽  
Ritwika Bhattacharya ◽  
Howard F. Jenkinson ◽  
Jeremy Derrick ◽  
...  
Keyword(s):  
Staphylococcus Epidermidis ◽  
Biofilm Formation ◽  
Domain Architecture ◽  
Opportunistic Pathogen ◽  
Additional Function ◽  
Artificial Joints ◽  
A Cell ◽  
Skin Colonization ◽  
Accumulation Associated Protein

ABSTRACT The opportunistic pathogen Staphylococcus epidermidis colonizes indwelling medical devices by biofilm formation but is primarily a skin resident. In many S. epidermidis strains biofilm formation is mediated by a cell wall-anchored protein, the accumulation-associated protein (Aap). Here, we investigate the role of Aap in skin adhesion. Aap is an LPXTG protein with a domain architecture including a terminal A domain and a B-repeat region. S. epidermidis NCTC 11047 expresses Aap as localized, lateral tufts of fibrils on one subpopulation of cells (Fib+), whereas a second subpopulation does not express these fibrils of Aap (Fib−). Flow cytometry showed that 72% of NCTC 11047 cells expressed Aap and that 28% of cells did not. Aap is involved in the adhesion of Fib+ cells to squamous epithelial cells from the hand (corneocytes), as the recombinant A-domain protein partially blocked binding to corneocytes. To confirm the role of the Aap A domain in corneocyte attachment, Aap was expressed on the surface of Lactococcus lactis MG1363 as sparsely distributed, peritrichous fibrils. The expression of Aap increased corneocyte adhesion 20-fold compared to L. lactis carrying Aap without an A domain. S. epidermidis isolates from catheters, artificial joints, skin, and the nose also used the A domain of Aap to adhere to corneocytes, emphasizing the role of Aap in skin adhesion. In addition, L. lactis expressing Aap with different numbers of B repeats revealed a positive correlation between the number of B repeats and adhesion to corneocytes, suggesting an additional function for the B region in enhancing A-domain-dependent attachment to skin. Therefore, in addition to its established role in biofilm formation, Aap can also promote adhesion to corneocytes and is likely to be an important adhesin in S. epidermidis skin colonization.

scholarly journals What’s a Biofilm?—How the Choice of the Biofilm Model Impacts the Protein Inventory of Clostridioides difficile

2021 ◽  
Vol 12 ◽  
Author(s):  
Madita Brauer ◽  
Christian Lassek ◽  
Christian Hinze ◽  
Juliane Hoyer ◽  
Dörte Becher ◽  
...  
Keyword(s):  
Cell Surface ◽  
Biofilm Formation ◽  
Surface Proteins ◽  
Type Iv ◽  
Clostridioides Difficile ◽  
Biofilm Model ◽  
Proteomics Approach ◽  
Surface Polysaccharides ◽  
Mammalian Intestine

The anaerobic pathogen Clostridioides difficile is perfectly equipped to survive and persist inside the mammalian intestine. When facing unfavorable conditions C. difficile is able to form highly resistant endospores. Likewise, biofilms are currently discussed as form of persistence. Here a comprehensive proteomics approach was applied to investigate the molecular processes of C. difficile strain 630Δerm underlying biofilm formation. The comparison of the proteome from two different forms of biofilm-like growth, namely aggregate biofilms and colonies on agar plates, revealed major differences in the formation of cell surface proteins, as well as enzymes of its energy and stress metabolism. For instance, while the obtained data suggest that aggregate biofilm cells express both flagella, type IV pili and enzymes required for biosynthesis of cell-surface polysaccharides, the S-layer protein SlpA and most cell wall proteins (CWPs) encoded adjacent to SlpA were detected in significantly lower amounts in aggregate biofilm cells than in colony biofilms. Moreover, the obtained data suggested that aggregate biofilm cells are rather actively growing cells while colony biofilm cells most likely severely suffer from a lack of reductive equivalents what requires induction of the Wood-Ljungdahl pathway and C. difficile’s V-type ATPase to maintain cell homeostasis. In agreement with this, aggregate biofilm cells, in contrast to colony biofilm cells, neither induced toxin nor spore production. Finally, the data revealed that the sigma factor SigL/RpoN and its dependent regulators are noticeably induced in aggregate biofilms suggesting an important role of SigL/RpoN in aggregate biofilm formation.

scholarly journals The role of luxS in Histophilus somni virulence and biofilm formation

2020 ◽  
Author(s):  
Yu Pan ◽  
Shivakumara Siddaramappa ◽  
Indra Sandal ◽  
Allan Dickerman ◽  
Aloka B. Bandara ◽  
...  
Keyword(s):  
Quorum Sensing ◽  
Biofilm Formation ◽  
Opportunistic Pathogen ◽  
Phenotypic Properties ◽  
Autoinducer 2 ◽  
Histophilus Somni ◽  
Signalling Molecule ◽  
The Matrix ◽  
Culture Supernatants

S-ribosylhomocysteinase (LuxS) is required for the synthesis of the autoinducer-2 (AI-2) quorum-sensing signalling molecule in many Gram-negative bacteria. The bovine (and ovine) opportunistic pathogen Histophilus somni contains a luxS, and forms a biofilm containing an exopolysaccharide (EPS) in the matrix. Since biofilm formation is regulated by quorum sensing in many bacteria, the role of luxS in H. somni virulence and biofilm formation was investigated. Although culture supernatants from H. somni were ineffective at inducing bioluminescence in the Vibrio harveyi reporter strain BB170, H. somni luxS complemented the biosynthesis of AI-2 in the luxS-deficient Escherichia coli strain DH5α. H. somni strain 2336 luxS was inactivated by tranposon mutagenesis. Comparison of RNA exression profiles revealed that many genes were significantly differentially expressed in the luxS mutant compared to the wildtype, whether the bacteria were grown planktonically or in a biofilm. Furthermore, the luxS mutant had a truncated and asialylated lipooligosaccharide (LOS), and was substantially more serum-sensitive than the wildtype. Not surprisingly, the luxS mutant was attenuated in a mouse model for H. somni virulence, and some of the altered phenotypes were partially restored after the mutation was complemented with a functional luxS. However, no major differences were observed between the wildtype and the luxS mutant in regard to outer membrane protein profiles, biofilm formation, EPS production, or intracellular survival. These results indicate that luxS plays a role in H. somni virulence in the context of LOS biosynthesis, but not biofilm formation or other phenotypic properties examined.

scholarly journals Sortase B, a New Class of Sortase in Listeria monocytogenes

2004 ◽  
Vol 186 (7) ◽  
pp. 1972-1982 ◽  
Author(s):  
Hélène Bierne ◽  
Caroline Garandeau ◽  
M. Graciela Pucciarelli ◽  
Christophe Sabet ◽  
Salete Newton ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Wall ◽  
Listeria Monocytogenes ◽  
Virulence Factor ◽  
Cultured Cells ◽  
Surface Proteins ◽  
Gram Positive Bacteria ◽  
New Class ◽  
Sorting Motif

ABSTRACT Sortases are transamidases that covalently link proteins to the peptidoglycan of gram-positive bacteria. The genome of the pathogenic bacterium Listeria monocytogenes encodes two sortases genes, srtA and srtB. The srtA gene product anchors internalin and some other LPXTG-containing proteins to the listerial surface. Here, we focus on the role of the second sortase, SrtB. Whereas SrtA acts on most of the proteins in the peptidoglycan fraction, SrtB appears to target minor amounts of surface polypeptides. We identified one of the SrtB-anchored proteins as the virulence factor SvpA, a surface-exposed protein which does not contain the LPXTG motif. Therefore, as in Staphylococcus aureus, the listerial SrtB represents a second class of sortase in L. monocytogenes, involved in the attachment of a subset of proteins to the cell wall, most likely by recognizing an NXZTN sorting motif. The ΔsrtB mutant strain does not have defects in bacterial entry, growth, or motility in tissue-cultured cells and does not show attenuated virulence in mice. SrtB-mediated anchoring could therefore be required to anchor surface proteins involved in the adaptation of this microorganism to different environmental conditions.

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