Polymyxins with Potent Antibacterial Activity against Colistin-Resistant Pathogens: Fine-Tuning Hydrophobicity with Unnatural Amino Acids
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Polymyxins with Potent Antibacterial Activity against Colistin-Resistant Pathogens : Fine-Tuning Hydrophobicity with Unnatural Amino Acids. / Jørgensen, Johan Storm; Mood, Elnaz Harifi; Knap, Anne Sofie Holst; Nielsen, Simone Eidnes; Nielsen, Peter E.; Żabicka, Dorota; Matias, Carina; Domraceva, Ilona; Björkling, Fredrik; Franzyk, Henrik.
In: Journal of Medicinal Chemistry, Vol. 67, No. 2, 2024, p. 1370–1383.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Polymyxins with Potent Antibacterial Activity against Colistin-Resistant Pathogens
T2 - Fine-Tuning Hydrophobicity with Unnatural Amino Acids
AU - Jørgensen, Johan Storm
AU - Mood, Elnaz Harifi
AU - Knap, Anne Sofie Holst
AU - Nielsen, Simone Eidnes
AU - Nielsen, Peter E.
AU - Żabicka, Dorota
AU - Matias, Carina
AU - Domraceva, Ilona
AU - Björkling, Fredrik
AU - Franzyk, Henrik
N1 - Publisher Copyright: © 2024 The Authors. Published by American Chemical Society.
PY - 2024
Y1 - 2024
N2 - In view of the increased prevalence of antimicrobial resistance among human pathogens, antibiotics against multidrug-resistant (MDR) bacteria are in urgent demand. In particular, the rapidly emerging resistance to last-resort antibiotic colistin, used for severe Gram-negative MDR infections, is critical. Here, a series of polymyxins containing unnatural amino acids were explored, and some analogues exhibited excellent antibacterial activity against Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa. Hydrophobicity of the compounds within this series (as measured by retention in reversed-phase analytical HPLC) exhibited a discernible correlation with their antimicrobial activity. This trend was particularly pronounced for colistin-resistant pathogens. The most active compounds demonstrated competitive activity against a panel of Gram-negative pathogens, while exhibiting low in vitro cytotoxicity. Importantly, most of these hits also retained (or even had increased) potency against colistin-susceptible strains. These findings infer that fine-tuning hydrophobicity may enable the design of polymyxin analogues with favorable activity profiles.
AB - In view of the increased prevalence of antimicrobial resistance among human pathogens, antibiotics against multidrug-resistant (MDR) bacteria are in urgent demand. In particular, the rapidly emerging resistance to last-resort antibiotic colistin, used for severe Gram-negative MDR infections, is critical. Here, a series of polymyxins containing unnatural amino acids were explored, and some analogues exhibited excellent antibacterial activity against Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa. Hydrophobicity of the compounds within this series (as measured by retention in reversed-phase analytical HPLC) exhibited a discernible correlation with their antimicrobial activity. This trend was particularly pronounced for colistin-resistant pathogens. The most active compounds demonstrated competitive activity against a panel of Gram-negative pathogens, while exhibiting low in vitro cytotoxicity. Importantly, most of these hits also retained (or even had increased) potency against colistin-susceptible strains. These findings infer that fine-tuning hydrophobicity may enable the design of polymyxin analogues with favorable activity profiles.
U2 - 10.1021/acs.jmedchem.3c01908
DO - 10.1021/acs.jmedchem.3c01908
M3 - Journal article
C2 - 38169430
AN - SCOPUS:85182002569
VL - 67
SP - 1370
EP - 1383
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 2
ER -
ID: 380201980