Symmetrically Substituted Xanthone Amphiphiles Combat Gram-Positive Bacterial Resistance with Enhanced Membrane Selectivity

This
is the first report of the design of a new series of symmetric
xanthone derivatives that mimic antimicrobial peptides using a total
synthesis approach. This novel design is advantageous because of its
low cost, synthetic simplicity and versatility, and easy tuning of
amphiphilicity by controlling the incorporated cationic and hydrophobic
moieties. Two water-soluble optimized compounds, 6 and 18, showed potent activities against Gram-positive bacteria,
including MRSA and VRE (MICs = 0.78–6.25 μg/mL) with
a rapid bactericidal effect, low toxicity, and no emergence of drug
resistance. Both compounds demonstrated enhanced membrane selectivity
that was higher than those of most membrane-active antimicrobials
in clinical trials or previous reports. The compounds appear to kill
bacteria by disrupting their membranes. Significantly, 6 was effective in vivo using a mouse model of corneal infection.
These results provide compelling evidence that these compounds have
therapeutic potential as novel antimicrobials for multidrug-resistant
Gram-positive infections.