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We found that the lasso peptide microcin J25 (MccJ25) and sulfamonomethoxine (SMM) disrupt transcription and folate biosynthesis, respectively, and act in synergy to inhibit bacterial growth and suppress resistance development.
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.