Structural highlights
Publication Abstract from PubMedWe report structural studies in aqueous solution on backbone cyclic peptides that possess potent antimicrobial activity specifically against Pseudomonas sp. The peptides target the beta-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 beta-hairpin structures in solution. In contrast, LB-02 is more flexible and importantly, adopts a wide variety of different backbone conformations, but not beta-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 beta-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 beta-hairpin represent key groups contributing to antimicrobial activity. Structural studies of beta-hairpin peptidomimetic antibiotics that target LptD in Pseudomonas sp.,Schmidt J, Patora-Komisarska K, Moehle K, Obrecht D, Robinson JA Bioorg Med Chem. 2013 Sep 15;21(18):5806-10. doi: 10.1016/j.bmc.2013.07.013. Epub, 2013 Jul 17. PMID:23932450[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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