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

Abstract

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.

Chiral Derivatives of Xanthones with Antimicrobial Activity

“…Cationic antimicrobial peptides (CAMPs) are amphipathic structures with hydrophobic and cationic groups that represent an effective component of the innate immune system against multiple microbes. These structures act by burring the hydrophobic moiety in the membranes core, while the cationic residues disrupt bacterial membrane [5,87,97,98]. Due to the manufacturing costs and poor stability of peptides, Koh et al [99] developed small molecules with CAMPs essential moieties ( 32 – 38S ) (Table 10).…”

<p>In vitro Antibacterial Activity of Isopropoxy Benzene Guanidine Against Multidrug-Resistant <em>Enterococci</em></p>

“…The time-dependent killing for E. faecalis ATCC 29212, MDR E. faecalis GDE6P130C and MDR E. faecium GDE6P50C with various concentrations of IBG, vancomycin (VAN) and linezolid (LNZ) were investigated. 22 The initial inoculum of 2×10 6 CFU/mL cells in 5 mL MH broth was challenged with IBG, VAN…”

Xanthones and Cancer: from Natural Sources to Mechanisms of Action

“…Aminoxanthones Selective amination, ketone-assisted, ruthenium-catalyzed [161,162] Amphiphilic xanthone Condensation of phloroglucinol and 2,4,6-trihydroxybenzoic acid in the presence of Eaton's reagent [163,164] Annulated xanthones Heck reaction/double CÀ H activation/retro-DielsÀ Alder [165] Azaxanthones Regioselective, Copper catalyzed, Ullmann coupling [166][167][168][169] Benzophenone xanthones…”