A Novel Small Molecule Accelerates Early Persister Regrowth and Potentiates Antibiotic Killing via MdtL-DcrB.

Abstract

Persister cells survive antibiotic exposure through transient tolerance, often leading to infection relapse. Because antibiotic susceptibility is restored when persisters resume growth, we sought to identify a chemical modulator that advances early regrowth and to define the pathway underlying its activity. A screen of 7040 compounds led to the discovery of bymBDZ, which shortens the lag phase and promotes early regrowth in persister-derived Escherichia coli. bymBDZ significantly enhanced antibiotic killing during early treatment windows when survivors are typically retained, and this activity extended to enterohemorrhagic E. coli O157:H7 and multiple antibiotic classes. Genetic and functional analyses showed that bymBDZ activity required the membrane transporter MdtL and the envelope factor DcrB. bymBDZ induced dcrB expression and remodelled envelope-associated transport, resulting in increased intracellular exposure to small molecules during early regrowth, as indicated by elevated dye accumulation. Consistent with this remodelling, bymBDZ promoted faster growth resumption and reinforced antibiotic killing during early regrowth. Collectively, these findings identify bymBDZ as a chemical probe that modulates persister regrowth through MdtL-DcrB-dependent envelope transport remodelling and suggest a strategy to sensitize tolerant bacteria to antibiotics.