Discovery of a specific inhibitor of pyomelanin synthesis in Legionella pneumophila

Oscar Aubi, Marte I. Flydal, Huaixin Zheng, Lars Skjærven, Illimar Rekand, Hanna Kirsti S. Leiros, Bengt Erik Haug, Nicholas P. Cianciotto, Aurora Martinez, Jarl Underhaug*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Phenylalanine hydroxylase catalyzes the first step in the synthesis of pyomelanin, a pigment that aids in the acquisition of essential iron in certain bacteria. In this work, we present the development and application of a drug discovery protocol by targeting this enzyme in Legionella pneumophila, the major causative agent of Legionnaires' disease. We employ a combination of high-throughput screening to identify small-molecule binders, enzymatic activity measurements to identify inhibitors in vitro, and the verification of the inhibitory effect in vivo. The most potent inhibitor shows an IC50 value in the low micromolar range and successfully abolishes the synthesis of pyomelanin in L. pneumophila cultures at 10 μM. Thus, this compound represents a novel and effective tool for investigating the role of pyomelanin in the biology and pathogenicity of this organism. Altogether, the results demonstrate a successful pathway for drug development focusing on binding specificity in the initial high-throughput screening steps.

Original languageEnglish (US)
Pages (from-to)8402-8412
Number of pages11
JournalJournal of Medicinal Chemistry
Volume58
Issue number21
DOIs
StatePublished - Nov 12 2015

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Fingerprint Dive into the research topics of 'Discovery of a specific inhibitor of pyomelanin synthesis in Legionella pneumophila'. Together they form a unique fingerprint.

Cite this