A dual-mechanism antibiotic kills Gram-negative bacteria and avoids drug resistance

The rise of antibiotic resistance and declining discovery of new
antibiotics have created a global health crisis. Of particular concern, no
new antibiotic classes have been approved for treating Gram-negative
pathogens in decades. Here, we characterize a compound, SCH-79797, that
kills both Gram-negative and Gram-positive bacteria through a unique
dual-targeting mechanism of action (MoA) with undetectably-low resistance
frequencies. To characterize its MoA, we combined quantitative imaging,
proteomic, genetic, metabolomic, and cell-based assays. This pipeline
demonstrates that SCH-79797 has two independent cellular targets, folate
metabolism and bacterial membrane integrity, and outperforms combination
treatments in killing MRSA persisters. Building on the molecular core of
SCH-79797, we developed a derivative, Irresistin-16, with increased
potency and showed its efficacy against Neisseria gonorrheae in a mouse
vaginal infection model. This promising antibiotic lead suggests that
combining multiple MoAs onto a single chemical scaffold may be an
underappreciated approach to targeting challenging bacterial pathogens.