Structural studies of β-hairpin peptidomimetic antibiotics that target LptD in Pseudomonas sp
2013
Schmidt, Jasmin | Patora-Komisarska, Krystyna | Moehle, Kerstin | Obrecht, Daniel | Robinson, John A.
We report structural studies in aqueous solution on backbone cyclic peptides that possess potent antimicrobial activity specifically against Pseudomonas sp. The peptides target the β-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 (T¹W²L³K⁴K⁵R⁶R⁷W⁸K⁹K¹⁰A¹¹K¹²) 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 DLys⁶ (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 β-hairpin structures in solution. In contrast, LB-02 is more flexible and importantly, adopts a wide variety of different backbone conformations, but not β-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 β-hairpin structure of the peptide is important for antimicrobial activity. An alanine scan of L27-11 revealed that tryptophan side chains (W²/W⁸) displayed on opposite faces of the β-hairpin represent key groups contributing to antimicrobial activity.
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