A periplasmic regulator establishes adaptive impermeability to control carbapenem entry

<jats:p>Outer-membrane permeability is a major determinant of antibiotic susceptibility in Gram-negative bacteria and is generally thought to be controlled through transcriptional regulation of porin expression. Here we identify the small periplasmic protein PtrA as a regulator of OprD-dependent carbapenem permeability in Pseudomonas aeruginosa. PtrA promotes imipenem resistance without altering OprD abundance, associates with OprD-containing membrane complexes and reduces intracellular imipenem entry. Using zinc and copper as complementary physiological signals, we show that PtrA-mediated permeability control is mechanistically distinct from CzcRS-dependent repression of oprD and precedes transcriptional porin depletion. These findings define a two-phase mechanism in which rapid periplasmic regulation provides an immediate adaptive response before transcriptional remodeling of the outer membrane. Our work identifies adaptive impermeability as a previously unrecognized mechanism linking environmental sensing to dynamic control of bacterial outer-membrane permeability.</jats:p>