N-alkyl substituted armeniaspirol analogs show potent antibiotic activity and have low susceptibility to resistance.

The armeniaspirol family of antibiotics have been shown to inhibit the ATP-dependent proteases ClpXP and ClpYQ and to disrupt the electrical membrane potential (ΔΨ) bacterial proton motive force. The synthesis and characterization of first generation armeniaspirol analogs shows the N-alkyl group is amenable to modification. Herein we synthesize eleven second generation N-alkyl analogs and show they display excellent antibiotic potency against multiple MRSA strains and retain the ability to disrupt membrane electrical potential. We also show that it is difficult to generate resistant MRSA mutants to these new compounds, making them appealing leads for new antibiotic development.