Rational design and synthesis of modified teixobactin analogues: in vitro antibacterial activity against Staphylococcus aureus, Propionibacterium acnes and Pseudomonas aeruginosa
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 replaceme...
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Wiley-VCH Verlag
2018
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| Online Access: | https://eprints.nottingham.ac.uk/51669/ |
| _version_ | 1848798547487490048 |
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| author | Ng, Vivian Kuehne, Sarah A. Chan, Weng |
| author_facet | Ng, Vivian Kuehne, Sarah A. Chan, Weng |
| author_sort | Ng, Vivian |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | 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. |
| first_indexed | 2025-11-14T20:21:30Z |
| format | Article |
| id | nottingham-51669 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| last_indexed | 2025-11-14T20:21:30Z |
| publishDate | 2018 |
| publisher | Wiley-VCH Verlag |
| recordtype | eprints |
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| spelling | nottingham-516692020-05-04T19:36:01Z https://eprints.nottingham.ac.uk/51669/ Rational design and synthesis of modified teixobactin analogues: in vitro antibacterial activity against Staphylococcus aureus, Propionibacterium acnes and Pseudomonas aeruginosa Ng, Vivian Kuehne, Sarah A. Chan, Weng 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. Wiley-VCH Verlag 2018-05-09 Article PeerReviewed Ng, Vivian, Kuehne, Sarah A. and Chan, Weng (2018) Rational design and synthesis of modified teixobactin analogues: in vitro antibacterial activity against Staphylococcus aureus, Propionibacterium acnes and Pseudomonas aeruginosa. Chemistry - a European Journal . ISSN 1521-3765 macrocyclic peptides; lipid II inhibitors; teixobactin; antimicrobial; colistin https://onlinelibrary.wiley.com/doi/abs/10.1002/chem.201801423 doi:10.1002/chem.201801423 doi:10.1002/chem.201801423 |
| spellingShingle | macrocyclic peptides; lipid II inhibitors; teixobactin; antimicrobial; colistin Ng, Vivian Kuehne, Sarah A. Chan, Weng Rational design and synthesis of modified teixobactin analogues: in vitro antibacterial activity against Staphylococcus aureus, Propionibacterium acnes and Pseudomonas aeruginosa |
| title | Rational design and synthesis of modified teixobactin analogues: in vitro antibacterial activity against Staphylococcus aureus, Propionibacterium acnes and Pseudomonas aeruginosa |
| title_full | Rational design and synthesis of modified teixobactin analogues: in vitro antibacterial activity against Staphylococcus aureus, Propionibacterium acnes and Pseudomonas aeruginosa |
| title_fullStr | Rational design and synthesis of modified teixobactin analogues: in vitro antibacterial activity against Staphylococcus aureus, Propionibacterium acnes and Pseudomonas aeruginosa |
| title_full_unstemmed | Rational design and synthesis of modified teixobactin analogues: in vitro antibacterial activity against Staphylococcus aureus, Propionibacterium acnes and Pseudomonas aeruginosa |
| title_short | Rational design and synthesis of modified teixobactin analogues: in vitro antibacterial activity against Staphylococcus aureus, Propionibacterium acnes and Pseudomonas aeruginosa |
| title_sort | rational design and synthesis of modified teixobactin analogues: in vitro antibacterial activity against staphylococcus aureus, propionibacterium acnes and pseudomonas aeruginosa |
| topic | macrocyclic peptides; lipid II inhibitors; teixobactin; antimicrobial; colistin |
| url | https://eprints.nottingham.ac.uk/51669/ https://eprints.nottingham.ac.uk/51669/ https://eprints.nottingham.ac.uk/51669/ |