This DECRA proposal uses novel genomics-based approaches to answer fundamental questions about how antibiotic synergy works. Antibiotic combination therapy presents a rare opportunity to revive antibiotics from the clutches of resistant bacteria, yet currently there is little understanding of the molecular mechanisms underlying antibiotic synergy. Preliminary work described here and a few studies indicate that additional mechanisms of action (MOA) occur during synergistic killing beyond those of the original antibiotics. This DECRA will identify genes involved in multiple synergistic treatments and determine how bacterial cells gain resistance. The synergyspecific MOA identified also represent an untapped reservoir of primary drug targets.