DPD-inspired discovery of novel LsrK kinase inhibitors: an opportunity to fight antimicrobial resistance

Silvia Stotani, Viviana Gatta, Prasanthi Medarametla, Mohan Padmanaban, Anna Karawajzyk, Fabrizio Giordanetto, Päivi Tammela, Tuomo Laitinen, Antti Poso, Dimitrios Tzalis, Simona Collina

Research output: Contribution to journalArticleScientificpeer-review

Abstract

Antibiotic resistance is posing a continuous threat to global public health and represents a huge burden for society as a whole. In the past decade, the interference with bacterial quorum sensing (QS) (i.e., cell cell communication) mechanisms has extensively been investigated as a valid therapeutic approach in the pursuit of a next generation of antimicrobials. (S)-4,5-Dihydroxy-2,3-pentanedione, commonly known as (S)-DPD, a small signaling molecule that modulates QS in both Gram-negative and Gram-positive bacteria, is phosphorylated by LsrK, and the resulting phospho-DPD activates QS. We designed and prepared a small library of DPD derivatives, characterized by five different scaffolds, and evaluated their LsrK inhibition in the context of QS interference. SAR studies highlighted the pyrazole moiety as an essential structural element for LsrK inhibition. Particularly, four compounds were found to be micromolar LsrK inhibitors (IC50 ranging between 100 mu M and 500 mu M) encouraging further exploration of novel analogues as potential new antimicrobials.

Original languageEnglish
JournalJournal of Medicinal Chemistry
Volume62
Issue number5
Pages (from-to)2720-2737
Number of pages18
ISSN0022-2623
DOIs
Publication statusPublished - 14 Mar 2019
MoE publication typeA1 Journal article-refereed

Fields of Science

  • AI-2
  • AUTOINDUCER-2
  • BIOFILM FORMATION
  • BIOLOGICAL-ACTIVITIES
  • ESCHERICHIA-COLI
  • ISOQUINOLINE ALKALOIDS
  • ONE-POT SYNTHESIS
  • QUORUM-SENSING SIGNAL
  • SALMONELLA-TYPHIMURIUM
  • VIBRIO-HARVEYI
  • 317 Pharmacy
  • 116 Chemical sciences

Cite this

Stotani, Silvia ; Gatta, Viviana ; Medarametla, Prasanthi ; Padmanaban, Mohan ; Karawajzyk, Anna ; Giordanetto, Fabrizio ; Tammela, Päivi ; Laitinen, Tuomo ; Poso, Antti ; Tzalis, Dimitrios ; Collina, Simona. / DPD-inspired discovery of novel LsrK kinase inhibitors: an opportunity to fight antimicrobial resistance. In: Journal of Medicinal Chemistry. 2019 ; Vol. 62, No. 5. pp. 2720-2737.
@article{36745594deff4ddcb9cb549bc5b2a705,
title = "DPD-inspired discovery of novel LsrK kinase inhibitors: an opportunity to fight antimicrobial resistance",
abstract = "Antibiotic resistance is posing a continuous threat to global public health and represents a huge burden for society as a whole. In the past decade, the interference with bacterial quorum sensing (QS) (i.e., cell cell communication) mechanisms has extensively been investigated as a valid therapeutic approach in the pursuit of a next generation of antimicrobials. (S)-4,5-Dihydroxy-2,3-pentanedione, commonly known as (S)-DPD, a small signaling molecule that modulates QS in both Gram-negative and Gram-positive bacteria, is phosphorylated by LsrK, and the resulting phospho-DPD activates QS. We designed and prepared a small library of DPD derivatives, characterized by five different scaffolds, and evaluated their LsrK inhibition in the context of QS interference. SAR studies highlighted the pyrazole moiety as an essential structural element for LsrK inhibition. Particularly, four compounds were found to be micromolar LsrK inhibitors (IC50 ranging between 100 mu M and 500 mu M) encouraging further exploration of novel analogues as potential new antimicrobials.",
keywords = "AI-2, AUTOINDUCER-2, BIOFILM FORMATION, BIOLOGICAL-ACTIVITIES, ESCHERICHIA-COLI, ISOQUINOLINE ALKALOIDS, ONE-POT SYNTHESIS, QUORUM-SENSING SIGNAL, SALMONELLA-TYPHIMURIUM, VIBRIO-HARVEYI, 317 Pharmacy, 116 Chemical sciences",
author = "Silvia Stotani and Viviana Gatta and Prasanthi Medarametla and Mohan Padmanaban and Anna Karawajzyk and Fabrizio Giordanetto and P{\"a}ivi Tammela and Tuomo Laitinen and Antti Poso and Dimitrios Tzalis and Simona Collina",
year = "2019",
month = "3",
day = "14",
doi = "10.1021/acs.jmedchem.9b00025",
language = "English",
volume = "62",
pages = "2720--2737",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
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Stotani, S, Gatta, V, Medarametla, P, Padmanaban, M, Karawajzyk, A, Giordanetto, F, Tammela, P, Laitinen, T, Poso, A, Tzalis, D & Collina, S 2019, 'DPD-inspired discovery of novel LsrK kinase inhibitors: an opportunity to fight antimicrobial resistance' Journal of Medicinal Chemistry, vol. 62, no. 5, pp. 2720-2737. https://doi.org/10.1021/acs.jmedchem.9b00025

DPD-inspired discovery of novel LsrK kinase inhibitors: an opportunity to fight antimicrobial resistance. / Stotani, Silvia; Gatta, Viviana; Medarametla, Prasanthi; Padmanaban, Mohan; Karawajzyk, Anna; Giordanetto, Fabrizio; Tammela, Päivi ; Laitinen, Tuomo; Poso, Antti; Tzalis, Dimitrios; Collina, Simona.

In: Journal of Medicinal Chemistry, Vol. 62, No. 5, 14.03.2019, p. 2720-2737.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - DPD-inspired discovery of novel LsrK kinase inhibitors: an opportunity to fight antimicrobial resistance

AU - Stotani, Silvia

AU - Gatta, Viviana

AU - Medarametla, Prasanthi

AU - Padmanaban, Mohan

AU - Karawajzyk, Anna

AU - Giordanetto, Fabrizio

AU - Tammela, Päivi

AU - Laitinen, Tuomo

AU - Poso, Antti

AU - Tzalis, Dimitrios

AU - Collina, Simona

PY - 2019/3/14

Y1 - 2019/3/14

N2 - Antibiotic resistance is posing a continuous threat to global public health and represents a huge burden for society as a whole. In the past decade, the interference with bacterial quorum sensing (QS) (i.e., cell cell communication) mechanisms has extensively been investigated as a valid therapeutic approach in the pursuit of a next generation of antimicrobials. (S)-4,5-Dihydroxy-2,3-pentanedione, commonly known as (S)-DPD, a small signaling molecule that modulates QS in both Gram-negative and Gram-positive bacteria, is phosphorylated by LsrK, and the resulting phospho-DPD activates QS. We designed and prepared a small library of DPD derivatives, characterized by five different scaffolds, and evaluated their LsrK inhibition in the context of QS interference. SAR studies highlighted the pyrazole moiety as an essential structural element for LsrK inhibition. Particularly, four compounds were found to be micromolar LsrK inhibitors (IC50 ranging between 100 mu M and 500 mu M) encouraging further exploration of novel analogues as potential new antimicrobials.

AB - Antibiotic resistance is posing a continuous threat to global public health and represents a huge burden for society as a whole. In the past decade, the interference with bacterial quorum sensing (QS) (i.e., cell cell communication) mechanisms has extensively been investigated as a valid therapeutic approach in the pursuit of a next generation of antimicrobials. (S)-4,5-Dihydroxy-2,3-pentanedione, commonly known as (S)-DPD, a small signaling molecule that modulates QS in both Gram-negative and Gram-positive bacteria, is phosphorylated by LsrK, and the resulting phospho-DPD activates QS. We designed and prepared a small library of DPD derivatives, characterized by five different scaffolds, and evaluated their LsrK inhibition in the context of QS interference. SAR studies highlighted the pyrazole moiety as an essential structural element for LsrK inhibition. Particularly, four compounds were found to be micromolar LsrK inhibitors (IC50 ranging between 100 mu M and 500 mu M) encouraging further exploration of novel analogues as potential new antimicrobials.

KW - AI-2

KW - AUTOINDUCER-2

KW - BIOFILM FORMATION

KW - BIOLOGICAL-ACTIVITIES

KW - ESCHERICHIA-COLI

KW - ISOQUINOLINE ALKALOIDS

KW - ONE-POT SYNTHESIS

KW - QUORUM-SENSING SIGNAL

KW - SALMONELLA-TYPHIMURIUM

KW - VIBRIO-HARVEYI

KW - 317 Pharmacy

KW - 116 Chemical sciences

U2 - 10.1021/acs.jmedchem.9b00025

DO - 10.1021/acs.jmedchem.9b00025

M3 - Article

VL - 62

SP - 2720

EP - 2737

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 5

ER -