1 Structural Studies of ß - Hairpin Antibiotics

We report structural studies in aqueous solution on backbone cyclic peptides that possess potent antimicrobial activity specifically against Pseudomonas sp. The peptides target the �-barrel outer membrane protein LptD, which plays an essential role in lipopolysaccharide transport to the outer membrane. The peptide L27-11 contains a 12-residue loop (T(1)W(2)L(3)K(4)K(5)R(6)R(7)W(8)K(9)K(10)A(11)K(12)) linked to a DPro-LPro template. Two related peptides were also studied, one with various Lys to ornithine or diaminobutyric acid substitutions as well as a DLys(6) (called LB-01), and another containing the same loop sequence, but linked to an LPro-DPro template (called LB-02). NMR studies and MD simulations show that L27-11 and LB-01 adopt �-hairpin structures in solution. In contrast, LB-02 is more flexible and importantly, adopts a wide variety of different backbone conformations, but not �-hairpin conformations. L27-11 and LB-01 show antimicrobial activity in the nanomolar range against Pseudomonas aeruginosa, whereas LB-02 is essentially inactive. Thus the �-hairpin structure of the peptide is important for antimicrobial activity. An alanine scan of L27-11 revealed that tryptophan side chains (W(2)/W(8)) displayed on opposite faces of the �-hairpin represent key groups contributing to antimicrobial activity. DOI: https://doi.org/10.1016/j.bmc.2013.07.013 Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-87738 Originally published at: Schmidt, Jasmin; Patora-Komisarska, Kristina; Moehle, Kerstin; Obrecht, Daniel; Robinson, John A (2013). Structural studies of �-hairpin peptidomimetic antibiotics that target LptD in Pseudomonas sp. Bioorganic Medicinal Chemistry, 21(18):5806-5810. DOI: https://doi.org/10.1016/j.bmc.2013.07.013