Membrane Active Small Molecules Show Selective Broad Spectrum Antibacterial Activity with No Detectable Resistance and Eradicate Biofilms

Treating bacterial biofilms with
conventional antibiotics is limited
due to ineffectiveness of the drugs and higher propensity to develop
bacterial resistance. Development of new classes of antibacterial
therapeutics with alternative mechanisms of action has become imperative.
Herein, we report the design, synthesis, and biological evaluations
of novel membrane-active small molecules featuring two positive charges,
four nonpeptidic amide groups, and variable hydrophobic/hydrophilic
(amphiphilic) character. The biocides synthesized via a facile methodology
not only displayed good antibacterial activity against wild-type bacteria
but also showed high activity against various drug-resistant bacteria
such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus faecium (VRE), and β-lactam-resistant Klebsiella pneumoniae. Further, these biocides not only inhibited the formation of biofilms
but also disrupted the established S. aureus and E. coli biofilms. The membrane-active biocides hindered
the propensity to develop bacterial resistance. Moreover, the biocides
showed negligible toxicity against mammalian cells and thus bear potential
to be used as therapeutic agents.