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Inhibitors of the Elastase LasB for the Treatment of Pseudomonas aeruginosa Lung Infections.
- Source :
-
ACS central science [ACS Cent Sci] 2023 Oct 27; Vol. 9 (12), pp. 2205-2215. Date of Electronic Publication: 2023 Oct 27 (Print Publication: 2023). - Publication Year :
- 2023
-
Abstract
- Infections 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.<br />Competing Interests: The authors declare the following competing financial interest(s): J.K., K.V., A.S.A., A.M.K., J.H., C.D., A.K.H.H., and R.W.H. are co-inventors on the international patent application (PCT/EP2021/073381) that incorporates methods outlined in this manuscript.<br /> (© 2023 The Authors. Published by American Chemical Society.)
Details
- Language :
- English
- ISSN :
- 2374-7943
- Volume :
- 9
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- ACS central science
- Publication Type :
- Academic Journal
- Accession number :
- 38161367
- Full Text :
- https://doi.org/10.1021/acscentsci.3c01102