PA5470 Counteracts Antimicrobial Effect of Azithromycin by Releasing Stalled Ribosome in Pseudomonas aeruginosa [PublishAheadOfPrint]

Pseudomonas aeruginosa causes various acute and chronic infections in human. Treatment with azithromycin (AZM) has been shown to benefit patients with chronic P. aeruginosa infections. By binding to the exit tunnel of 50S ribosome, AZM causes ribosome stalling and depletion of intracellular tRNA pool. It has been shown that AZM is able to kill stationary-phase P. aeruginosa cells and repress quorum sensing regulated virulence factors as well as swarming motility. In P. aeruginosa, PA5470 encodes a putative peptide chain release factor, whose expression is highly induced by macrolide antibiotics. However, its function remains unknown. Here we found that overexpression of PA5470 increased bacterial tolerance against AZM and alleviated the repression of swarming motility. Ribosome pull-down assays revealed that PA5470 contributes to the release of ribosome stalled by the AZM. We further demonstrate that overexpression of PA5470 counteracts AZM mediated repression on the translation of the quorum sensing regulator RhlR. Overall, our results revealed a novel role of PA5470 in bacterial response to AZM.

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