Abstract
New drugs are urgently required to address the ongoing health crisis caused by methicillin-resistant Staphylococcus aureus (MRSA) infections. Added to the challenge is the difficult-to-treat persister cells and biofilm which are tolerant to the antibiotics. Here we report a new approach to these problems, describing the design and synthesis of aminoxy-acid-based dipeptides that facilitate cation transport across cell membranes to disrupt bacterial ion homeostasis. Remarkably, these synthetic cation transporters display significant antibacterial activity against MRSA, while maintaining high selectivity over mammalian cells. They also effectively eliminate bacterial persisters and reduce established biofilms. Additionally, they inhibit biofilm formation and suppress bacterial virulent protein secretion, even at subinhibitory concentrations. Their associated antibiotic effects support their in vivo efficacy in murine skin and bloodstream MRSA infection models with no observable toxicity to the host. Mode-of-action analysis indicates that these cation transporters induce cytoplasmic acidification, hyperpolarization, and calcium influx, accelerating autolysis. Given their potent activity against bacterial persisters and biofilms, synthetic cation transporters are an emergent and promising class of compounds in the fight against MRSA infections.