Virtual Screening Approach to Identifying a Novel and Tractable Series of<i>Pseudomonas aeruginosa</i>Elastase Inhibitors

Abstract

Novel therapies are required to treat chronic bacterial infections in cystic fibrosis (CF) sufferers. The most common pathogen responsible for these infections is <i>Pseudomonas aeruginosa</i>, which persists within the lungs of CF sufferers despite intensive antibiotic treatment. <i>P. aeruginosa</i> elastase (also known as LasB or pseudolysin) is a key virulence determinant that contributes to the pathogenesis and persistence of <i>P. aeruginosa</i> infections in CF patients. The crucial role of LasB in pseudomonal virulence makes it a good target for the development of an adjuvant drug for CF treatment. Herein we discuss the discovery of a new series of LasB inhibitors by virtual screening and computer assisted drug design (CADD) and their optimization leading to compounds <b>29</b> and <b>39</b> (<i>K</i> _i = 0.16 μM and 0.12 μM, respectively).