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

被引:5
作者
Ballante, Flavio [1 ]
Turkina, Maria V. [2 ]
Ntzouni, Maria [3 ]
Magnusson, Karl-Eric [2 ]
Vikstrom, Elena [2 ]
机构
[1] Karolinska Inst, Chem Biol Consortium Sweden CBCS, Sci Life Lab, Dept Med Biochem & Biophys, Stockholm, Sweden
[2] Linkoping Univ, Fac Med & Hlth Sci, Dept Biomed & Clin Sci, Linkoping, Sweden
[3] Linkoping Univ, Fac Med & Hlth Sci, Core Facil, Linkoping, Sweden
基金
瑞典研究理事会;
关键词
Pseudomonas aeruginosa; quorum sensing; antivirulence strategy; small-molecule probes; N-acyl-L-homoserine lactone; LasR; molecular docking; structure-based drug design; BIOLOGICAL EVALUATION; RECEPTOR LASR; INHIBITORS; VIRULENCE; IDENTIFICATION; SYSTEMS; ANTAGONISTS; PROTEIN; CYTOTOXICITY; MODULATORS;
D O I
10.3389/fmolb.2023.1264773
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 beta-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.
引用
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页数:22
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