Identification and Structure–Activity Relationships of Novel Compounds that Potentiate the Activities of Antibiotics in Escherichia coli

In
Gram-negative bacteria, efflux pumps are able to prevent effective
cellular concentrations from being achieved for a number of antibiotics.
Small molecule adjuvants that act as efflux pump inhibitors (EPIs)
have the potential to reinvigorate existing antibiotics that are currently
ineffective due to efflux mechanisms. Through a combination of rigorous
experimental screening and in silico virtual screening, we recently
identified novel classes of EPIs that interact with the membrane fusion
protein AcrA, a critical component of the AcrAB-TolC efflux pump in Escherichia coli. Herein, we present initial optimization
efforts and structure–activity relationships around one of
those previously described hits, NSC 60339 (1). From
these efforts we identified two compounds, SLUPP-225 (17h) and SLUPP-417 (17o), which demonstrate favorable properties as potential
EPIs in E. coli cells including the
ability to penetrate the outer membrane, improved inhibition of efflux
relative to 1, and potentiation of the activity of novobiocin
and erythromycin.