Binding Mode Characterization and Early in Vivo Evaluation of Fragment-Like Thiols as Inhibitors of the Virulence Factor LasB from Pseudomonas aeruginosa

authored by

Andreas M. Kany, Asfandyar Sikandar, Jörg Haupenthal, Samir Yahiaoui, Christine K. Maurer, Ewgenij Proschak, Jesko Köhnke, Rolf W. Hartmann

Abstract

The increasing emergence of antibiotic resistance necessitates the development of anti-infectives with novel modes of action. Targeting bacterial virulence is considered a promising approach to develop novel antibiotics with reduced selection pressure. The extracellular collagenase elastase (LasB) plays a pivotal role in the infection process of Pseudomonas aeruginosa and therefore represents an attractive antivirulence target. Mercaptoacetamide-based thiols have been reported to inhibit LasB as well as collagenases from clostridia and bacillus species. The present work provides an insight into the structure-activity relationship (SAR) of these fragment-like LasB inhibitors, demonstrating an inverse activity profile compared to similar inhibitors of clostridial collagenase H (ColH). An X-ray cocrystal structure is presented, revealing distinct binding of two compounds to the active site of LasB, which unexpectedly maintains an open conformation. We further demonstrate in vivo efficacy in a Galleria mellonella infection model and high selectivity of the LasB inhibitors toward human matrix metalloproteinases (MMPs).

External Organisation(s)

Saarland University
Goethe University Frankfurt
Helmholtz Institute for Pharmaceutical Research Saarland (HIPS)

Type

Article

Journal

ACS infectious diseases

Volume

4

Pages

988-997

No. of pages

10

ISSN

2373-8227

Publication date

08.06.2018

Publication status

Published

Peer reviewed

Yes

ASJC Scopus subject areas

Infectious Diseases

Sustainable Development Goals

SDG 3 - Good Health and Well-being

Electronic version(s)

https://doi.org/10.1021/acsinfecdis.8b00010 (Access: Closed)