Open AccessPositional Isomers of Biphenyl Antimicrobial Peptidomimetic Amphiphiles
Author(s) -
Andrew J. Tague,
Papanin Putsathit,
Thomas V. Riley,
P. A. Keller,
Stephen G. Pyne
Publication year - 2021
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.0c00611
Subject(s) - antimicrobial , enterococcus faecalis , peptidomimetic , acinetobacter baumannii , streptococcus pneumoniae , chemistry , bacteria , pseudomonas aeruginosa , microbiology and biotechnology , staphylococcus aureus , escherichia coli , antibacterial activity , stereochemistry , biology , antibiotics , peptide , biochemistry , genetics , gene
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 ).