Covalent Proteomimetic Inhibitor of the Bacterial FtsQB Divisome Complex.

Autor: Paulussen FM; Department of Chemistry and Pharmaceutical Sciences, Vrije Universiteit Amsterdam, De Boelelaan 1085, Amsterdam 1081 HV, Netherlands.; Amsterdam Institute of Molecular and Life Sciences (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1085, Amsterdam 1081 HV, Netherlands.; Department of Molecular Microbiology, Vrije Universiteit Amsterdam, De Boelelaan 1085, Amsterdam 1081 HV, Netherlands., Schouten GK; Medical Microbiology and Infection Control (MMI), Amsterdam UMC Location VUmc, De Boelelaan 1108, Amsterdam 1081 HZ, Netherlands., Moertl C; Department of Chemistry and Pharmaceutical Sciences, Vrije Universiteit Amsterdam, De Boelelaan 1085, Amsterdam 1081 HV, Netherlands.; Amsterdam Institute of Molecular and Life Sciences (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1085, Amsterdam 1081 HV, Netherlands., Verheul J; Department of Bacterial Cell Biology and Physiology, Swammerdam Institute for Life Sciences, University of Amsterdam, Sciencepark 904, Amsterdam 1098 XH, Netherlands., Hoekstra I; Department of Chemistry and Pharmaceutical Sciences, Vrije Universiteit Amsterdam, De Boelelaan 1085, Amsterdam 1081 HV, Netherlands., Koningstein GM; Amsterdam Institute of Molecular and Life Sciences (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1085, Amsterdam 1081 HV, Netherlands.; Department of Molecular Microbiology, Vrije Universiteit Amsterdam, De Boelelaan 1085, Amsterdam 1081 HV, Netherlands., Hutchins GH; Department of Chemistry and Pharmaceutical Sciences, Vrije Universiteit Amsterdam, De Boelelaan 1085, Amsterdam 1081 HV, Netherlands.; Amsterdam Institute of Molecular and Life Sciences (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1085, Amsterdam 1081 HV, Netherlands., Alkir A; Department of Chemistry and Pharmaceutical Sciences, Vrije Universiteit Amsterdam, De Boelelaan 1085, Amsterdam 1081 HV, Netherlands., Luirink RA; Department of Chemistry and Pharmaceutical Sciences, Vrije Universiteit Amsterdam, De Boelelaan 1085, Amsterdam 1081 HV, Netherlands.; Amsterdam Institute of Molecular and Life Sciences (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1085, Amsterdam 1081 HV, Netherlands., Geerke DP; Department of Chemistry and Pharmaceutical Sciences, Vrije Universiteit Amsterdam, De Boelelaan 1085, Amsterdam 1081 HV, Netherlands.; Amsterdam Institute of Molecular and Life Sciences (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1085, Amsterdam 1081 HV, Netherlands., van Ulsen P; Amsterdam Institute of Molecular and Life Sciences (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1085, Amsterdam 1081 HV, Netherlands.; Department of Molecular Microbiology, Vrije Universiteit Amsterdam, De Boelelaan 1085, Amsterdam 1081 HV, Netherlands., den Blaauwen T; Department of Bacterial Cell Biology and Physiology, Swammerdam Institute for Life Sciences, University of Amsterdam, Sciencepark 904, Amsterdam 1098 XH, Netherlands., Luirink J; Amsterdam Institute of Molecular and Life Sciences (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1085, Amsterdam 1081 HV, Netherlands.; Department of Molecular Microbiology, Vrije Universiteit Amsterdam, De Boelelaan 1085, Amsterdam 1081 HV, Netherlands., Grossmann TN; Department of Chemistry and Pharmaceutical Sciences, Vrije Universiteit Amsterdam, De Boelelaan 1085, Amsterdam 1081 HV, Netherlands.; Amsterdam Institute of Molecular and Life Sciences (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1085, Amsterdam 1081 HV, Netherlands.
Jazyk: angličtina
Zdroj: Journal of the American Chemical Society [J Am Chem Soc] 2022 Aug 24; Vol. 144 (33), pp. 15303-15313. Date of Electronic Publication: 2022 Aug 09.
DOI: 10.1021/jacs.2c06304
Abstrakt: The use of antibiotics is threatened by the emergence and spread of multidrug-resistant strains of bacteria. Thus, there is a need to develop antibiotics that address new targets. In this respect, the bacterial divisome, a multi-protein complex central to cell division, represents a potentially attractive target. Of particular interest is the FtsQB subcomplex that plays a decisive role in divisome assembly and peptidoglycan biogenesis in E. coli . Here, we report the structure-based design of a macrocyclic covalent inhibitor derived from a periplasmic region of FtsB that mediates its binding to FtsQ. The bioactive conformation of this motif was stabilized by a customized cross-link resulting in a tertiary structure mimetic with increased affinity for FtsQ. To increase activity, a covalent handle was incorporated, providing an inhibitor that impedes the interaction between FtsQ and FtsB irreversibly . The covalent inhibitor reduced the growth of an outer membrane-permeable E. coli strain, concurrent with the expected loss of FtsB localization, and also affected the infection of zebrafish larvae by a clinical E. coli strain. This first-in-class inhibitor of a divisome protein-protein interaction highlights the potential of proteomimetic molecules as inhibitors of challenging targets. In particular, the covalent mode-of-action can serve as an inspiration for future antibiotics that target protein-protein interactions.
Databáze: MEDLINE
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