2. Academic Validation
  3. Positional Isomers of Biphenyl Antimicrobial Peptidomimetic Amphiphiles

Positional Isomers of Biphenyl Antimicrobial Peptidomimetic Amphiphiles

  • ACS Med Chem Lett. 2021 Feb 3;12(3):413-419. doi: 10.1021/acsmedchemlett.0c00611.
Andrew J Tague 1,  Papanin Putsathit 2,  Thomas V Riley 2 3 4 5,  Paul A Keller 1,  Stephen G Pyne 1
Affiliations

Affiliations

  • 1 School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, New South Wales 2522, Australia.
  • 2 School of Medical and Health Sciences, Edith Cowan University, Joondalup, Western Australia 6027, Australia.
  • 3 PathWest Laboratory Medicine, Queen Elizabeth II Medical Centre, Nedlands, Western Australia 6009, Australia.
  • 4 School of Biomedical Sciences, Faculty of Health and Medical Sciences, The University of Western Australia, Queen Elizabeth II Medical Centre, Nedlands, Western Australia 6009, Australia.
  • 5 Medical, Molecular and Forensic Sciences, Murdoch University, Murdoch, Western Australia 6150, Australia.
PMID: 33738069 DOI: 10.1021/acsmedchemlett.0c00611
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).

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