The MarR family regulator RmaH underlies the trade-off between acid sensitivity and antibiotic tolerance in Lactococcus lactis.

UNLABELLED: Microorganisms exhibit remarkable adaptability to diverse environmental stresses through transcriptional reprogramming. Here, we focused on the MarR family regulator RmaH in Lactococcus lactis, which orchestrated a pivotal trade-off: enhancing tolerance to the bacteriocin nisin and the antibiotic vancomycin at the expense of acid resistance. RmaH directly activated genes for cell wall and membrane lipid biosynthesis, leading to a thicker cell wall, and repressed the arginine deiminase pathway, attenuating acid tolerance. Integrated transcriptomic, chromatin immunoprecipitation-sequencing, and electrophoretic mobility shift assay identified RmaH as a global transcription regulator, modulating processes, including amino acid transport and metabolism, cell wall/membrane/envelope biogenesis, carbohydrate transport and metabolism, and nucleotide transport and metabolism. The molecular basis of this regulation was defined by identifying two RmaH-specific DNA-binding motifs and confirming the essential role of arginine residues R79 and R87 in DNA binding. Our work elucidated a sophisticated regulatory mechanism that enabled bacteria to navigate complex and changing stressors.

IMPORTANCE: This study reveals how the global regulator RmaH in Lactococcus lactis orchestrates a critical survival trade-off, prioritizing antibiotic tolerance over acid resistance. By directly activating cell wall and membrane biosynthesis pathways, RmaH enhances defense against antimicrobials like nisin and vancomycin. Concurrently, it represses the arginine deiminase pathway, compromising the cell's ability to mitigate acid stress. This work provides a fundamental model for how bacteria dynamically allocate finite cellular resources to navigate complex, changing environments. The elucidated mechanism offers broader insights into bacterial persistence strategies and the physiological compromises underlying stress response networks.