Adaptive landscape of the metallo-β-lactamase NDM-1 to emerging β-lactam-based therapies.

Different β-lactam therapies impose distinct evolutionary constraints on NDM-1, with escape mutations identified for mecillinam and taniborbactam but not for aztreonam or xeruborbactam.

• Why it matters: Understanding how NDM-1 evolves under various therapeutic pressures is crucial for predicting resistance development and guiding effective treatment strategies against carbapenem-resistant infections.
• What they did: A diverse library of bla NDM variants was challenged with zinc limitation, antibiotics, or β-lactam/β-lactamase inhibitor combinations, revealing drug-specific mutational pathways and constraints.
• The result: Findings show that some therapies, like taniborbactam, readily select for enzyme escape mutations, while others, such as aztreonam and xeruborbactam, did not yield resistant NDM variants, informing resistance risk assessment.