Human Single-Chain Antibodies That Neutralize Elastolytic Activity of Pseudomonas aeruginosa LasB

Santajit, Sirijan; Kong-Ngoen, Thida; Chongsa-nguan, Manas; Boonyuen, Usa; Pumirat, Pornpan; Sookrung, Nitat; Chaicumpa, Wanpen; Indrawattana, Nitaya

doi:10.3390/pathogens10060765

Cited by 10 publications

(7 citation statements)

References 58 publications

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“…Concerning stability and selectivity, replacement of the ZBG could be an interesting opportunity since some functional groups have not been explored yet, such as boronate (vaborbactam) or phosphonate, which have recently shown their ability to strongly inhibit other bacterial collagenases with promising selectivity and stability profiles [ 22 ]. Other strategies can be considered to overcome the perpetual challenge of selective metalloprotease inhibition, such as the use of antibodies [ 50 ].…”

Section: Discussionmentioning

confidence: 99%

The Structures and Binding Modes of Small-Molecule Inhibitors of Pseudomonas aeruginosa Elastase LasB

et al. 2022

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Elastase B (LasB) is a zinc metalloprotease and a crucial virulence factor of Pseudomonas aeruginosa. As the need for new strategies to fight antimicrobial resistance (AMR) constantly rises, this protein has become a key target in the development of novel antivirulence agents. The extensive knowledge of the structure of its active site, containing two subpockets and a zinc atom, led to various structure-based medicinal chemistry programs and the optimization of several chemical classes of inhibitors. This review provides a brief reminder of the structure of the active site and a summary of the disclosed P. aeruginosa LasB inhibitors. We specifically focused on the analysis of their binding modes with a detailed representation of them, hence giving an overview of the strategies aiming at targeting LasB by small molecules.

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Section: Discussionmentioning

confidence: 99%

The Structures and Binding Modes of Small-Molecule Inhibitors of Pseudomonas aeruginosa Elastase LasB

et al. 2022

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“…The synthesis of rhamnolipids requires RhlA regulation (Van Gennip et al, 2009). LasB can degrade immunoglobulins, complement, and cytokines (Bastaert et al, 2018; Santajit et al, 2021). The host immune system may be harmed by rhamnolipids, which can cause host neutrophil necrosis (Jensen et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

The involvement of the T6SS vgrG gene in the pathogenicity of Pseudomonas plecoglossicida

Yang,

Zhao,

et al. 2023

Journal of Fish Diseases

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Pseudomonas plecoglossicida, the causative agent of white spot disease of large yellow croaker, has caused serious economic losses to the aquaculture industry. The type VI secretion system (T6SS) is a significant virulence system widely distributed among Gram‐negative bacteria. VgrG, a structural and core component of T6SS, is crucial to the function of T6SS. To explore the biological profiles mediated by vgrG gene and its effects on the pathogenicity of P. plecoglossicida, the vgrG gene deletion (ΔvgrG) strain and complementary (C‐ΔvgrG) strain were constructed and the differences in pathogenicity and virulence‐related characteristics between different strains were analysed. The results showed that vgrG gene deletion significantly affected the virulence‐related characteristics of P. plecoglossicida, including chemotaxis, adhesion, and biofilm formation. In addition, the LD50 of ΔvgrG strain was nearly 50‐fold higher than that of the NZBD9 strain. Transcriptome data analysis suggested that the vgrG gene may affect the virulence of P. plecoglossicida by regulating the quorum sensing pathway to inhibit the secretion of virulence factors and affect biofilm formation. Besides, deletion of the vgrG gene may reduce bacterial pathogenicity by affecting bacterial signal transduction processes and the ability to adapt to chemotactic substances.

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“…The LasB activity was also determined using the EnzChek Elastase Assay Kit (Invitrogen, Carlsbad, USA, 2407850), following the method described by Santajit et al (Santajit et al 2021 ). The 96-well microplate was incubated in darkness at 37 °C, and the fluorescence intensity was monitored dynamically every 10 min for 2.5 h (Ex/Em = 485 nm/530 nm) using the Cytation™ 3 Cell Imaging Multi-Mode Reader (BioTek Instruments Co., Ltd., Vermont, USA).…”

Section: Methodsmentioning

confidence: 99%

Quercetin: a promising virulence inhibitor of Pseudomonas aeruginosa LasB in vitro

Ren,

Zhu,

You

et al. 2024

Appl Microbiol Biotechnol

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With the inappropriate use of antibiotics, antibiotic resistance has emerged as a major dilemma for patients infected with Pseudomonas aeruginosa. Elastase B (LasB), a crucial extracellular virulence factor secreted by P. aeruginosa, has been identified as a key target for antivirulence therapy. Quercetin, a natural flavonoid, exhibits promising potential as an antivirulence agent. We aim to evaluate the impact of quercetin on P. aeruginosa LasB and elucidate the underlying mechanism. Molecular docking and molecular dynamics simulation revealed a rather favorable intermolecular interaction between quercetin and LasB. At the sub-MICs of ≤256 μg/ml, quercetin was found to effectively inhibit the production and activity of LasB elastase, as well as downregulate the transcription level of the lasB gene in both PAO1 and clinical strains of P. aeruginosa. Through correlation analysis, significant positive correlations were shown between the virulence gene lasB and the QS system regulatory genes lasI, lasR, rhlI, and rhlR in clinical strains of P. aeruginosa. Then, we found the lasB gene expression and LasB activity were significantly deficient in PAO1 ΔlasI and ΔlasIΔrhlI mutants. In addition, quercetin significantly downregulated the expression levels of regulated genes lasI, lasR, rhlI, rhlR, pqsA, and pqsR as well as effectively attenuated the synthesis of signaling molecules 3-oxo-C12-HSL and C4-HSL in the QS system of PAO1. Quercetin was also able to compete with the natural ligands OdDHL, BHL, and PQS for binding to the receptor proteins LasR, RhlR, and PqsR, respectively, resulting in the formation of more stabilized complexes. Taken together, quercetin exhibits enormous potential in combating LasB production and activity by disrupting the QS system of P. aeruginosa in vitro, thereby offering an alternative approach for the antivirulence therapy of P. aeruginosa infections. Key points • Quercetin diminished the content and activity of LasB elastase of P. aeruginosa. • Quercetin inhibited the QS system activity of P. aeruginosa. • Quercetin acted on LasB based on the QS system.

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Human Single-Chain Antibodies That Neutralize Elastolytic Activity of Pseudomonas aeruginosa LasB

Cited by 10 publications

References 58 publications

The Structures and Binding Modes of Small-Molecule Inhibitors of Pseudomonas aeruginosa Elastase LasB

The Structures and Binding Modes of Small-Molecule Inhibitors of Pseudomonas aeruginosa Elastase LasB

The involvement of the T6SS vgrG gene in the pathogenicity of Pseudomonas plecoglossicida

Quercetin: a promising virulence inhibitor of Pseudomonas aeruginosa LasB in vitro

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