Disrupting Transcription and Folate Biosynthesis Leads to Synergistic Suppression of Escherichia coli Growth

The use of synergistic antibiotic combinations has emerged as a viable approach to contain the rapid spread of antibiotic‐resistant pathogens. Here we report the discovery of a new strongly synergistic pair – microcin J25 and sulfamonomethoxine. The former is a lasso peptide that inhibits the function of RNA polymerase and the latter is a sulfonamide antibacterial agent that disrupts the folate pathway. Key to our discovery was a screening strategy that focuses on an antibiotic (microcin J25) that targets a hub (transcription) in the densely interconnected network of cellular pathways. The rationale was that disrupting such a hub likely weakens the entire network, generating weak links that potentiate the growth inhibitory effect of other antibiotics. We found that MccJ25 potentiates five other antibiotics as well. These results showcase the merit of taking a more targeted approach in the search and study of synergistic antibiotic pairs. The lasso peptide microcin J25 and sulfamonomethoxine each disrupt a hub, transcription and folate biosynthesis, respectively, in the intricately interconnected cellular network. They act in synergy to inhibit bacterial growth and suppress resistance development.