10.1002/anie.201901589
Angewandte Chemie International Edition
COMMUNICATION
. Time course of normalized pyranine fluorescence after addition of: A
Figure 5. Time course of normalized pyranine fluorescence after addition of the following compounds. A and B: 5 µM to 50 nM 1 (P:L 1:10 to 1:1000)
with A: proton influx from pH 6.4 to 7.4, B: proton efflux from pH 7.4 to 8.4. C: After addition of 1 µM (P:L 1:50) 11, 25 and 1, proton influx from pH 6.4
and B 5 µM to 50 nM 1 (P:L 1:10 to 1:1000) with A: proton influx from pH 6.4
to 7.4. Vesicles composed of POPC, total lipid concentration 50 µM, containing 0.5 mM pyranine.
to 7.4, B: proton efflux from pH 7.4 to 8.4. C: After addition of 1 µM (P:L 1:50)
In summary, we established an optimized synthesis of 1 to Conflict of interest
provide access to manifold analogues. By SAR studies, we
revealed the essential motifs for antimicrobial activity, notably, the
alternation of D- and L-amino acids, the presence of tryptophan
and leucine as well as the N-unsubstituted thiazolidine. The
identical activity of the enantiomer 22 suggested that chiral
recognition was not relevant for the MoA of 1. Additionally, 1 and
its analogues illustrate a strong correlation between membrane
depolarization and MIC values with S. aureus cells. Furthermore,
1 did not induce large pores neither in S. aureus cells nor in POPC
vesicles and acts via proton translocation in synthetic membrane
vesicles. In addition, the two-fold more active 23 (Trp6) verified
Eberhard Karls University Tübingen holds a patent for lugdunin
(EP3072899B1).
Keywords: thiazolidine antibiotic • proton translocation •
synthetic membrane vesicles • MRSA • aldehyde peptide
synthesis
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Acknowledgements
Work of N.A.S. is supported by the Institutional Strategy of the
University of Tübingen (DFG, ZUK 63). The authors are grateful
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