TY  - JOUR
AU  - Porta, Nicola
AU  - Zaschke-Kriesche, Julia
AU  - Frieg, Benedikt
AU  - Gopalswamy, Mohanraj
AU  - Zivkovic, Aleksandra
AU  - Etzkorn, Manuel
AU  - Stark, Holger
AU  - Smits, Sander H. J.
AU  - Gohlke, Holger
TI  - Small-molecule inhibitors of nisin resistance protein NSR from the human pathogen Streptococcus agalactiae
JO  - Bioorganic & medicinal chemistry
VL  - 27
IS  - 20
SN  - 0968-0896
CY  - Amsterdam [u.a.]
PB  - Elsevier
M1  - FZJ-2019-04532
SP  - 115079
PY  - 2019
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:31500943
UR  - <Go to ISI:>//WOS:000486383500014
DO  - DOI:10.1016/j.bmc.2019.115079
UR  - https://juser.fz-juelich.de/record/864929
ER  -