TY - JOUR
T1 - Rational design and synthesis of modified teixobactin analogues:
T2 - in vitro antibacterial activity against Staphylococcus aureus, Propionibacterium acnes and Pseudomonas aeruginosa
AU - Ng, Vivian
AU - Kuehne, Sarah A
AU - Chan, Weng
PY - 2018/5/9
Y1 - 2018/5/9
N2 - Teixobactin, a recently discovered depsipeptide that binds to bacterial lipid II and lipid III, provides a promising molecular scaffold for the design of new antimicrobials. Herein, we describe the synthesis and antimicrobial evaluation of systematically modified teixobactin analogues. The replacement of Ile11 residue with aliphatic isosteres, the modification of the guanidino group at residue 10 and the introduction of a rigidifying residue, dehydroamino acid into the macrocyclic ring generated useful structure‐activity information. Extensive antimicrobial susceptibility assessment against a panel of clinically relevant Staphylococcus aureus and Propionibacterium acnes led to the identification of a new lead compound, [Arg(Me)10,Nle11]teixobactin 63, with excellent bactericidal activity (MIC 2‐4 μg/mL). Significantly, the antimicrobial activity of several of the teixobactin analogues against the pathogenic Gram‐negative Pseudomonas aeruginosa was 'restored' when combined with sub‐MIC concentration of the outer membrane‐disruptive antibiotic, colistin. The antimicrobial effectiveness of [Tfn10,Nle11]teixobactin 66 (32 μg/mL)‐colistin (2 μg/mL; 0.5x MIC) combination against P. aeruginosa PAO1 reveal, for the first time, an alternative therapeutic option in the treatment of Gram‐negative infections.
AB - Teixobactin, a recently discovered depsipeptide that binds to bacterial lipid II and lipid III, provides a promising molecular scaffold for the design of new antimicrobials. Herein, we describe the synthesis and antimicrobial evaluation of systematically modified teixobactin analogues. The replacement of Ile11 residue with aliphatic isosteres, the modification of the guanidino group at residue 10 and the introduction of a rigidifying residue, dehydroamino acid into the macrocyclic ring generated useful structure‐activity information. Extensive antimicrobial susceptibility assessment against a panel of clinically relevant Staphylococcus aureus and Propionibacterium acnes led to the identification of a new lead compound, [Arg(Me)10,Nle11]teixobactin 63, with excellent bactericidal activity (MIC 2‐4 μg/mL). Significantly, the antimicrobial activity of several of the teixobactin analogues against the pathogenic Gram‐negative Pseudomonas aeruginosa was 'restored' when combined with sub‐MIC concentration of the outer membrane‐disruptive antibiotic, colistin. The antimicrobial effectiveness of [Tfn10,Nle11]teixobactin 66 (32 μg/mL)‐colistin (2 μg/mL; 0.5x MIC) combination against P. aeruginosa PAO1 reveal, for the first time, an alternative therapeutic option in the treatment of Gram‐negative infections.
KW - macrocyclic peptides
KW - lipid II inhibitors
KW - teixobactin
KW - antimicrobial
KW - colistin
U2 - 10.1002/chem.201801423
DO - 10.1002/chem.201801423
M3 - Article
SN - 0947-6539
JO - Chemistry: A European Journal
JF - Chemistry: A European Journal
ER -