# Glnk Mediates Carbapenem Resistance Through the NtrB/NtrC-OprD Regulatory Pathway in Pseudomonas aeruginosa

## TL;DR

This study reveals how a gene mutation in Pseudomonas aeruginosa affects carbapenem resistance through a regulatory pathway involving nitrogen metabolism.

## Contribution

The discovery of a new regulatory pathway linking GlnK, NtrB/NtrC, and OprD to carbapenem resistance in P. aeruginosa.

## Key findings

- A mutation in the glnK gene decreases carbapenem resistance in P. aeruginosa.
- The NtrB/NtrC system regulates oprD, which is crucial for carbapenem uptake.
- Deleting ntrB, ntrC, or oprD in the glnK mutant restores carbapenem resistance.

## Abstract

Pseudomonas aeruginosa is a major causative agent of nosocomial infections worldwide. Carbapenems are the first-line agents for combating severe P. aeruginosa infections. However, the increasing prevalence of carbapenem-resistant P. aeruginosa (CRPA) has developed as a critical threat to global healthcare systems. In this study, we demonstrated that a mutation in the core nitrogen metabolism regulatory gene glnK decreases carbapenem resistance in P. aeruginosa. OprD, the major porin for carbapenem uptake, is upregulated in the glnK mutant, resulting in decreased resistance. We further found that the NtrB/NtrC two-component regulatory system is upregulated in the glnK mutant. An electrophoretic mobility shift assay (EMSA) and genetic studies revealed a direct regulatory role of NtrC on the expression of oprD. Deletion of ntrB, ntrC, or oprD in the glnK mutant restored the bacterial resistance to carbapenems. These results reveal that a GlnK-NtrB/NtrC-OprD regulatory pathway affects carbapenem resistance, shedding light on the regulatory relationship between nitrogen metabolism and carbapenem resistance in P. aeruginosa.