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Positional Isomers of Biphenyl Antimicrobial Peptidomimetic Amphiphiles

Journal Article


Abstract


  • Small-molecule antimicrobial peptidomimetic amphiphiles represent a promising class of novel antimicrobials with the potential for widespread therapeutic application. To investigate the role of spatial positioning for key hydrophobic and hydrophilic groups on the antimicrobial efficacy and selectivity, positional isomers of the lead biphenyl antimicrobial peptidomimetic compound 1 were synthesized and subjected to microbial growth inhibition and mammalian toxicity assays. Positional isomer 4 exhibited 4-8× increased efficacy against the pathogenic Gram-negative bacteria Pseudomonas aeruginosa and Escherichia coli (MIC = 2 μg/mL), while isomers 2, 3, and 7 exhibited a 4× increase in activity against Acinetobacter baumannii (MIC = 4 μg/mL). Changes in molecular shape had a significant impact on Gram-negative antibacterial efficacy and the resultant spectrum of activity, whereas all structural isomers exhibited significant efficacy (MIC = 0.25-8 μg/mL) against Gram-positive bacterial pathogens (e.g., methicillin-resistant Staphylococcus aureus, Streptococcus pneumoniae, and Enterococcus faecalis).

Publication Date


  • 2021

Citation


  • Tague, A. J., Putsathit, P., Riley, T. V., Keller, P. A., & Pyne, S. G. (2021). Positional Isomers of Biphenyl Antimicrobial Peptidomimetic Amphiphiles. ACS Medicinal Chemistry Letters, 12(3), 413-419. doi:10.1021/acsmedchemlett.0c00611

Scopus Eid


  • 2-s2.0-85101031031

Start Page


  • 413

End Page


  • 419

Volume


  • 12

Issue


  • 3

Abstract


  • Small-molecule antimicrobial peptidomimetic amphiphiles represent a promising class of novel antimicrobials with the potential for widespread therapeutic application. To investigate the role of spatial positioning for key hydrophobic and hydrophilic groups on the antimicrobial efficacy and selectivity, positional isomers of the lead biphenyl antimicrobial peptidomimetic compound 1 were synthesized and subjected to microbial growth inhibition and mammalian toxicity assays. Positional isomer 4 exhibited 4-8× increased efficacy against the pathogenic Gram-negative bacteria Pseudomonas aeruginosa and Escherichia coli (MIC = 2 μg/mL), while isomers 2, 3, and 7 exhibited a 4× increase in activity against Acinetobacter baumannii (MIC = 4 μg/mL). Changes in molecular shape had a significant impact on Gram-negative antibacterial efficacy and the resultant spectrum of activity, whereas all structural isomers exhibited significant efficacy (MIC = 0.25-8 μg/mL) against Gram-positive bacterial pathogens (e.g., methicillin-resistant Staphylococcus aureus, Streptococcus pneumoniae, and Enterococcus faecalis).

Publication Date


  • 2021

Citation


  • Tague, A. J., Putsathit, P., Riley, T. V., Keller, P. A., & Pyne, S. G. (2021). Positional Isomers of Biphenyl Antimicrobial Peptidomimetic Amphiphiles. ACS Medicinal Chemistry Letters, 12(3), 413-419. doi:10.1021/acsmedchemlett.0c00611

Scopus Eid


  • 2-s2.0-85101031031

Start Page


  • 413

End Page


  • 419

Volume


  • 12

Issue


  • 3