posted on 2020-11-24, 01:45authored bySarah
J. Perlmutter, Emily J. Geddes, Bryon S. Drown, Stephen E. Motika, Myung Ryul Lee, Paul J. Hergenrother
Multidrug-resistant
Gram-negative bacterial infections are on the
rise, and with no FDA approvals for new classes of broad-spectrum
antibiotics in over 50 years, these infections constitute a major
threat to human health. A significant challenge is the inability of
most compounds to accumulate in Gram-negative bacteria. Recently developed
predictive guidelines show that appending a primary amine to an appropriately
shaped compound can enhance Gram-negative accumulation. Here, we report
that other positively charged nitrogen functional groups, namely, N-alkyl guanidiniums and pyridiniums, can also facilitate
compound uptake into Gram-negative bacteria. The accumulation of a
set of 60 nonantibiotic compounds, consisting of 20 primary amines
and their corresponding guanidiniums and pyridiniums, was assessed
in Escherichia coli. We also installed these alternate
functional groups onto antibiotic scaffolds and assessed their accumulation
and antibacterial activity in Gram-negative bacteria. The results
suggest that other positively-charged, nitrogen-containing functional
groups should be considered when designing antibiotics with Gram-negative
activity.