Structural studies of β-hairpin peptidomimetic antibiotics that target LptD in Pseudomonas sp.
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 (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 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 (W(2)/W(8)) displayed on opposite faces of the β-hairpin represent key groups contributing to antimicrobial activity.
Chemistry Department, University of Zurich, Switzerland.
Jasmin
J
Schmidt
Krystyna
K
Patora-Komisarska
Kerstin
K
Moehle
Daniel
D
Obrecht
John A
JA
Robinson
D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D001425:Bacterial Outer Membrane Proteins / Q000737:chemistry* / Q000378:metabolism; D002942:Circular Dichroism; D008826:Microbial Sensitivity Tests; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D057786:Peptidomimetics; D017433:Protein Structure, Secondary; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000378:metabolism*; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D001425:Bacterial Outer Membrane Proteins; D010455:Peptides; D057786:Peptidomimetics
Antibacterial; Conformation; Lipopolysaccharide transport; Peptide; Peptidomimetic; Pseudomonas aeruginosa; β-Barrel membrane protein