What Makes Pseudomonas aeruginosa a Pathogen?

Tümmler, Burkhard

doi:10.1007/978-3-031-08491-1_10

Cited by 5 publications

(14 citation statements)

References 138 publications

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“…Furthermore, using phenotypic assays, we tested the effect of our compounds on the activity and production of various virulence traits, such as proteases, elastase, pyocyanin, and extracellular DNA in P. aeruginosa PA14. Many extracellular enzymes with proteolytic activity are regulated by Las and Rhl circuits, including the 33-kDa elastase B being involved in the pathogenesis by acting on many substrates, e.g., elastin, collagen types II and IV, fibronectin, and immunoglobulin A, thereby degrading mucosal and connective tissues and preventing bacterial clearance ( Pont et al, 2022 ; Tummler, 2022 ). Pseudomonas aeruginosa also secretes pyocyanin, which is a blue–green-colored phenazine, redox-active, toxic secondary metabolite.…”

Section: Discussionmentioning

confidence: 99%

“…As a human opportunistic pathogen, it is one of the leading causes of nosocomial severe infections located in various host tissues, particularly in patients with impaired immunity and compromised natural barriers. If not properly eradicated during acute illnesses, P. aeruginosa can establish chronic conditions that are even more difficult to treat ( Pont et al, 2022 ; Tummler, 2022 ). This is partly due because bacteria create and live as a biofilm, i.e., a small ecosystem associated with a surface and embedded in a self-producing matrix of macromolecules.…”

Section: Introductionmentioning

confidence: 99%

“…This biofilm provides a sustainable community with highly coordinated production of virulent determinants and increased resistance to the immune system and drugs ( Hoiby et al, 2010 ; Breidenstein et al, 2011 ; Poole, 2011 ). Moreover, P. aeruginosa is equipped with a broad array of virulence traits and sophisticated molecular mechanisms that allow the bacteria to accommodate their lifestyle, manipulate host–pathogen interactions, and escape host defense ( Pont et al, 2022 ; Tummler, 2022 ). The plasticity of the P. aeruginosa genome, supported by global regulatory networks, is a central feature in the pathogen’s ability to adapt and survive within the host.…”

Section: Introductionmentioning

confidence: 99%

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Modified N-acyl-L-homoserine lactone compounds abrogate Las-dependent quorum-sensing response in human pathogen Pseudomonas aeruginosa

Ballante,

Turkina,

Ntzouni

et al. 2023

Front. Mol. Biosci.

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Quorum sensing (QS) is a mode of cell–cell communication that bacteria use to sense population density and orchestrate collective behaviors. The common opportunistic human pathogen Pseudomonas aeruginosa employs QS to regulate a large set of genes involved in virulence and host–pathogen interactions. The Las circuit positioned on the top of the QS hierarchy in P. aeruginosa makes use of N-acyl-L-homoserine lactones (AHLs) as signal molecules, like N-3-oxo-dodecanoyl-L-homoserine lactone (3O-C12-HSL). Disabling QS circuits by certain small-molecule compounds, known as quorum-sensing inhibitors (QSIs), has been proposed as a strategy to attenuate bacterial pathogenicity. In this study, four new AHL analogs were designed by incorporating a tert-butoxycarbonyl Boc group in amide and β-keto (3-oxo) moiety. Compounds were evaluated on a molecular and phenotypic basis as a QSI using the screening strategy linked to the assignment of the Las QS system in P. aeruginosa. Using a LasR-based bioreporter, we found that the compounds decreased LasR-controlled light activity and competed efficiently with natural 3O-C12-HSL. The compounds reduced the production of the cognate 3O-C12-HSL and certain virulence traits, like total protease activity, elastase activity, pyocyanin production, and extracellular DNA release. Furthermore, a quantitative proteomic approach was used to study the effect of the compounds on QS-regulated extracellular proteins. Among the four compounds tested, one of them showed the most significant difference in the appearance of the 3O-C12-HSL-responsive reference proteins related to QS communication and virulence, i.e., a distinct activity as a QSI. Moreover, by combining experimental data with computational chemistry, we addressed the effect of LasR protein flexibility on docking precision and assessed the advantage of using a multi-conformational docking procedure for binding mode prediction of LasR modulators. Thus, the four new AHL compounds were tested for their interaction with the AHL-binding site in LasR to identify the key interferences with the activity of LasR. Our study provides further insight into molecular features that are required for small-molecule modulation of LasR-dependent QS communication in P. aeruginosa. This should facilitate rational design of the next generation of antivirulence tools to study and manipulate QS-controlled fitness in bacteria and, thereby, handle bacterial infections in a new way.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Modified N-acyl-L-homoserine lactone compounds abrogate Las-dependent quorum-sensing response in human pathogen Pseudomonas aeruginosa

Ballante,

Turkina,

Ntzouni

et al. 2023

Front. Mol. Biosci.

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show abstract

“…Pseudomonas aeruginosa is a metabolically versatile aquatic gamma-proteobacterium that colonizes animate surfaces of plants, animals and humans [1]. During the last decades, this cosmopolitan Gramnegative bacterium has become one of the most frequent causative agents of nosocomial infections associated with substantial morbidity and mortality [1]. Chronic airway infections with P. aeruginosa are a major cause of morbidity in people with cystic fibrosis (CF), chronic obstructive pulmonary disease or bronchiectasis.…”

mentioning

confidence: 99%

“…Thus, the majority of people with bronchiectasis should have acquired P. aeruginosa from other sources, most likely from the inanimate environment. P. aeruginosa is ubiquitously present in aquatic habitats [1]. All organisms including humans are exposed to this bacterium, albeit usually far below the threshold of an infectious dose and culture-based microbiology diagnostics [1].…”

mentioning

confidence: 99%