Description: Small-molecule inhibitors of nisin resistance protein NSR from the human pathogen Streptococcus agalactiae

This title appears in the Scientific Report : 2019

Small-molecule inhibitors of nisin resistance protein NSR from the human pathogen Streptococcus agalactiae

Lantibiotics are antimicrobial peptides produced by Gram-positive bacteria and active in the nanomolar range. Nisin is the most intensely studied and used lantibiotic, with applications as food preservative and recognized potential for clinical usage. However, different bacteria that are pathogenic...

Personal Name(s):	Porta, Nicola
	Zaschke-Kriesche, Julia / Frieg, Benedikt / Gopalswamy, Mohanraj / Zivkovic, Aleksandra / Etzkorn, Manuel / Stark, Holger / Smits, Sander H. J. / Gohlke, Holger (Corresponding author)
Contributing Institute:	Strukturbiochemie; ICS-6 John von Neumann - Institut für Computing; NIC Jülich Supercomputing Center; JSC
Published in:	Bioorganic & medicinal chemistry, 27 (2019) 20, S. 115079
Imprint:	Amsterdam [u.a.] Elsevier 2019
PubMed ID:	31500943
DOI:	10.1016/j.bmc.2019.115079
Document Type:	Journal Article
Research Program:	Forschergruppe Gohlke Physical Basis of Diseases Computational Science and Mathematical Methods
Link:	Published on 2019-08-26. Available in OpenAccess from 2021-08-26. Published on 2019-08-26. Available in OpenAccess from 2021-08-26.
	Publikationsportal JuSER

Please use the identifier: http://hdl.handle.net/2128/22917 in citations.
Please use the identifier: http://dx.doi.org/10.1016/j.bmc.2019.115079 in citations.

Lantibiotics are antimicrobial peptides produced by Gram-positive bacteria and active in the nanomolar range. Nisin is the most intensely studied and used lantibiotic, with applications as food preservative and recognized potential for clinical usage. However, different bacteria that are pathogenic for humans and do not produce nisin, including Streptococcus agalactiae, show an innate resistance that has been related to the nisin resistance protein (NSR), a membrane-associated protease. Here, we report the first-in-class small-molecule inhibitors of SaNSR identified by virtual screening based on a previously derived structural model of the nisin/NSR complex. The inhibitors belong to three different chemotypes, of which the halogenated phenyl-urea derivative NPG9 is the most potent one. Co-administration of NPG9 with nisin yields increased potency compared to nisin alone in SaNSR-expressing bacteria. The binding mode of NPG9, predicted with molecular docking and validated by extensive molecular dynamics simulations, confirms a structure-activity relationship derived from the in vivo data. Saturation transfer difference-NMR experiments demonstrate direct binding of NPG9 to SaNSR and agree with the predicted binding mode. Our results demonstrate the potential to overcome SaNSR-related lantibiotic resistance by small molecules.