Modifications to a Biphenolic Antibacterial Compound: Activity against ESKAPE Pathogens.

Forty-four analogs of honokiol, a compound with known antibacterial activity, especially with respect to oral bacteria, were synthesized to explore the structure-activity relationships against the ESKAPE pathogens. Compounds with high therapeutic indices (hemolysis 20 /MIC) were identified. In particular, ester-linked compounds that would be less than environmentally durable than biaryl ether antibacterials such as the broadly used triclosan were found to be active. MRSA mutants could be generated against some, but not all, of the highly active compounds. Based on gene sequencing results, membrane permeability, intracellular sodium, and intracellular pH assays revealed overlapping mechanisms of action.