A surprising link between copper homeostasis and bacterial multiple antibiotic resistance

In all organisms, copper is an essential micronutrient, required for the activity of enzymes involved in respiration and redox homeostasis. However, copper is also highly cytotoxic, and therefore it is carefully delivered only to its designated targets. Surprisingly, very little is known about the process of bacterial copper acquisition and delivery.

In a previous work we identified a 3-gene cluster (an operon) with copper-responsive transcriptional elements in its promoter region. We found that this operon (hereafter the AZY operon) codes for two periplasmic proteins, one which binds copper with very high affinity and the other with very low affinity.

Herein we report that the third protein is a copper transporter, that imports copper into the bacterial cell. Surprisingly, we find that the copper imported by the AZY protein is instrumental in activating the bacterial Multiple Antibiotic Resistance (MAR) response. We propose that bacterial envelope damage caused by antibiotics exposure allows copper to leak into the periplasm. This copper is then delivered by the AZY proteins to the MAR repressor MarR. Copper binding to MarR leads to its dissociation from the DNA, enabling activation of the MAR response and bacterial multiple antibiotic resistance.