8cc4
LasB bound to phosphonic acid based inhibitorLasB bound to phosphonic acid based inhibitor
Structural highlights
FunctionELAS_PSEAE Cleaves elastin, collagen, IgG, and several complement components. Involved in the pathogenesis of P.aeruginosa infections. Publication Abstract from PubMedInfections caused by the Gram-negative pathogen Pseudomonas aeruginosa are emerging worldwide as a major threat to human health. Conventional antibiotic monotherapy suffers from rapid resistance development, underlining urgent need for novel treatment concepts. Here, we report on a nontraditional approach to combat P. aeruginosa-derived infections by targeting its main virulence factor, the elastase LasB. We discovered a new chemical class of phosphonates with an outstanding in vitro ADMET and PK profile, auspicious activity both in vitro and in vivo. We established the mode of action through a cocrystal structure of our lead compound with LasB and in several in vitro and ex vivo models. The proof of concept of a combination of our pathoblocker with levofloxacin in a murine neutropenic lung infection model and the reduction of LasB protein levels in blood as a proof of target engagement demonstrate the great potential for use as an adjunctive treatment of lung infections in humans. Inhibitors of the Elastase LasB for the Treatment of Pseudomonas aeruginosa Lung Infections.,Konstantinovic J, Kany AM, Alhayek A, Abdelsamie AS, Sikandar A, Voos K, Yao Y, Andreas A, Shafiei R, Loretz B, Schonauer E, Bals R, Brandstetter H, Hartmann RW, Ducho C, Lehr CM, Beisswenger C, Muller R, Rox K, Haupenthal J, Hirsch AKH ACS Cent Sci. 2023 Oct 27;9(12):2205-2215. doi: 10.1021/acscentsci.3c01102. , eCollection 2023 Dec 27. PMID:38161367[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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