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Structure–activity relationships for inhibitors of Pseudomonas aeruginosa exoenzyme S ADP-ribosyltransferase activity
Umeå University, Faculty of Science and Technology, Department of Chemistry.ORCID iD: 0000-0003-2721-6074
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
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2018 (English)In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 143, p. 568-576Article in journal (Refereed) Published
Abstract [en]

During infection, the Gram-negative opportunistic pathogen Pseudomonas aeruginosa employs its type III secretion system to translocate the toxin exoenzyme S (ExoS) into the eukaryotic host cell cytoplasm. ExoS is an essential in vivo virulence factor that enables P. aeruginosa to avoid phagocytosis and eventually kill the host cell. ExoS elicits its pathogenicity mainly via ADP-ribosyltransferase (ADPRT) activity. We recently identified a new class of ExoS ADPRT inhibitors with in vitro IC50 of around 20 μM in an enzymatic assay using a recombinant ExoS ADPRT domain. Herein, we report structure-activity relationships of this compound class by comparing a total of 51 compounds based on a thieno [2,3-d]pyrimidin-4(3H)-one and 4-oxo-3,4-dihydroquinazoline scaffolds. Improved inhibitors with in vitro IC50 values of 6 μM were identified. Importantly, we demonstrated that the most potent inhibitors block ADPRT activity of native full-length ExoS secreted by viable P. aeruginosa with an IC50 value of 1.3 μM in an enzymatic assay. This compound class holds promise as starting point for development of novel antibacterial agents.

Place, publisher, year, edition, pages
Elsevier, 2018. Vol. 143, p. 568-576
Keywords [en]
2-Aminobenzamide, ADP-Ribosyltransferase, Bacterial exotoxins, ExoS, Pseudomonas aeruginosa, Quinazolines, Type III secretion
National Category
Organic Chemistry Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-143429DOI: 10.1016/j.ejmech.2017.11.036ISI: 000428216700046PubMedID: 29207339OAI: oai:DiVA.org:umu-143429DiVA, id: diva2:1169324
Available from: 2017-12-23 Created: 2017-12-23 Last updated: 2018-08-24Bibliographically approved
In thesis
1. Towards novel antibacterials: Synthesis and identification of natural product inspired inhibitors of Chlamydia trachomatis and development of chemical probes targeting virulence of Pseudomonas aeruginosa
Open this publication in new window or tab >>Towards novel antibacterials: Synthesis and identification of natural product inspired inhibitors of Chlamydia trachomatis and development of chemical probes targeting virulence of Pseudomonas aeruginosa
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Antibiotic resistance has evolved significantly to become one of the serious threats to public health today. Yet, the pipeline of new antibiotics is drying up and is lagging behind the challenging needs. As a contribution to this recurrent need for novel antibacterials, we applied multidisciplinary strategies to identify small-molecule antibacterials against Chlamydia trachomatis and antivirulence agents against Pseudomonas aeruginosa infections. These strategies included:

1. Synthesis of a focused compounds library inspired by natural product scaffolds followed by phenotypic screening against Chlamydia trachomatis. (Paper I)

(-)-Hopeaphenol is a polyphenol natural product that was identified as an antivirulence agent against Y. pseudotuberculosis and P. aeruginosa. Hopeaphenol core scaffold, 2,3-diaryl-2,3-dihydrobenzofuran, is ubiquitous in polyphenolic phytochemicals. In this thesis, a focused library of forty-eight compounds was synthesized based on 2,3-diarylbenzofuran and 2,3-diaryl-2,3- dihydrobenzofuran. The library was then explored for antibacterial properties in a number of screening assays and resulted in five novel antichlamydial compounds with inhibition potency down to sub-micromolar. The identified molecules also inhibited the growth of different clinical presentations of C. trachomatis, one of the most common sexually transmitted disease worldwide.

2. Target-based screening against the P. aeruginosa virulence factor using enzymatic and biophysical assays. (Paper II-IV)

P. aeruginosa is a Gram-negative opportunistic pathogen with remarkable antibiotic resistance that is associated with a wide range of clinical infections. An alternative strategy to develop novel and selective antibacterials is to target the bacterial virulence factors, i.e. the ability of the bacteria to promote disease, thus ‘disarming’ the pathogens instead of killing them. P. aeruginosa employs its virulence factor, the type III secretion system (T3SS), to inject toxins (e.g. ExoS) into the eukaryotic cytosol. In one part of this thesis, we utilized enzymatic assay and identified inhibitors against the P. aeruginosa T3S toxin (ExoS). A follow up structure-activity relationship analysis was established and resulted in five (low micromolar) inhibitors of ExoS ADP-ribosylation enzymatic activity. In another part, we used surface plasmon resonance biophysical assay and identified small molecule binders of T3S translocation protein (PcrV). The primary SAR analysis was established and showed the antivirulence properties of these molecules and the potential to expand them further as novel antibacterials.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2018. p. 95
Keywords
Antibacterials, antibiotics, small molecules, natural products, benzofuran, dihydrobenzofuran, the type III secretion system, Pseudomonas aeruginosa, Chlamydia trachomatis, phenotypic screening, high-throughput screening, surface plasmon resonance, drug discovery, bacterial toxins, enzyme inhibitors
National Category
Natural Sciences Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-150970 (URN)978-91-7601-917-7 (ISBN)
Public defence
2018-09-14, KB.E3.03 (Stora hörsalen), KBC-huset, Umeå, 09:00 (English)
Opponent
Supervisors
Funder
Swedish Foundation for Strategic Research , SSF, SB12-0022
Available from: 2018-08-24 Created: 2018-08-21 Last updated: 2018-08-21Bibliographically approved

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Saleeb, MichaelSundin, CharlottaForsberg, ÅkeElofsson, Mikael
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