Toxin-mediated depletion of NAD and NADP drives persister formation in a human pathogen.

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 8208664 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1460-2075 (Electronic) Linking ISSN: 02614189 NLM ISO Abbreviation: EMBO J Subsets: MEDLINE

Publication: 2024- : [London] : Nature Publishing Group
Original Publication: Eynsham, Oxford, England : Published for the European Molecular Biology Organization by IRL Press, [c1982-

Pseudomonas aeruginosa*/metabolism ; Pseudomonas aeruginosa*/genetics ; Pseudomonas aeruginosa*/pathogenicity ; NAD*/metabolism ; Toxin-Antitoxin Systems*/genetics ; NADP*/metabolism; Humans ; Bacterial Toxins/metabolism ; Bacterial Toxins/genetics ; Bacterial Proteins/metabolism ; Bacterial Proteins/genetics ; Virulence ; Pseudomonas Infections/microbiology ; Pseudomonas Infections/metabolism

Toxin-antitoxin (TA) systems are widespread in bacteria and implicated in genome stability, virulence, phage defense, and persistence. TA systems have diverse activities and cellular targets, but their physiological roles and regulatory mechanisms are often unclear. Here, we show that the NatR-NatT TA system, which is part of the core genome of the human pathogen Pseudomonas aeruginosa, generates drug-tolerant persisters by specifically depleting nicotinamide dinucleotides. While actively growing P. aeruginosa cells compensate for NatT-mediated NAD ⁺ deficiency by inducing the NAD ⁺ salvage pathway, NAD depletion generates drug-tolerant persisters under nutrient-limited conditions. Our structural and biochemical analyses propose a model for NatT toxin activation and autoregulation and indicate that NatT activity is subject to powerful metabolic feedback control by the NAD ⁺ precursor nicotinamide. Based on the identification of natT gain-of-function alleles in patient isolates and on the observation that NatT increases P. aeruginosa virulence, we postulate that NatT modulates pathogen fitness during infections. These findings pave the way for detailed investigations into how a toxin-antitoxin system can promote pathogen persistence by disrupting essential metabolic pathways.
(© 2024. The Author(s).)

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310030_189253 Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (SNF); 51NF40_180541 National Center of Competence in Research AntiResist (NCCR AntiResist)

Keywords: Pseudomonas aeruginosa; NADase; Persisters; RES Domain; Toxin–antitoxin System

0U46U6E8UK (NAD)
53-59-8 (NADP)
0 (Bacterial Toxins)
0 (Bacterial Proteins)

Date Created: 20240925 Date Completed: 20241105 Latest Revision: 20241107

20250114

PMC11535050

10.1038/s44318-024-00248-5

39322758