Abstract
Bacterial toxin–antitoxin complexes are emerging as key players modulating bacterial physiology as activation of toxins induces stasis or programmed cell death by interference with vital cellular processes. Zeta toxins, which are prevalent in many bacterial genomes, were shown to interfere with cell wall formation by perturbing peptidoglycan synthesis in Gram-positive bacteria. Here, we characterize the epsilon/zeta toxin–antitoxin (TA) homologue from the Gram-negative pathogen Neisseria gonorrhoeae termed ng_ɛ1 / ng_ζ1. Contrary to previously studied streptococcal epsilon/zeta TA systems, ng_ɛ1 has an epsilon-unrelated fold and ng_ζ1 displays broader substrate specificity and phosphorylates multiple UDP-activated sugars that are precursors of peptidoglycan and lipopolysaccharide synthesis. Moreover, the phosphorylation site is different from the streptococcal zeta toxins, resulting in a different interference with cell wall synthesis. This difference most likely reflects adaptation to the individual cell wall composition of Gram-negative and Gram-positive organisms but also the distinct involvement of cell wall components in virulence.
Highlights
Bacterial toxin–antitoxin complexes are emerging as key players modulating bacterial physiology as activation of toxins induces stasis or programmed cell death by interference with vital cellular processes
When comparing the configuration of UNAM bound to ngζ_1 with UNAG bound to S. pyogenes zeta toxin[21], we found a UDP-sugar binding mode to the active site that follows a rigid-body rotation by 180° (Supplementary Fig. 7), causing that the C4′-OH and not the C3′-OH group is located in close proximity to the catalytic important aspartic acid (Asp[56] in ngζ_1 and Asp[67] in S. pyogenes zeta toxin)
We have studied the gonococcal ngζ_1 as the paradigm for a hitherto unknown class of abundant zeta kinases that are wired topologically different when compared to previously characterized zeta toxins of Gram-positive bacteria
Summary
Bacterial toxin–antitoxin complexes are emerging as key players modulating bacterial physiology as activation of toxins induces stasis or programmed cell death by interference with vital cellular processes. Zeta toxins, which are prevalent in many bacterial genomes, were shown to interfere with cell wall formation by perturbing peptidoglycan synthesis in Grampositive bacteria. TA modules were initially discovered as plasmid stabilizing systems, but have since been shown to regulate persister cell and biofilm formation, to act as stress response elements and even to increase virulence of pathogenic bacteria[5,6,7]. Because of their roles in bacterial survival, TA systems have become interesting targets for the development of new antimicrobial agents. The combined types of MurA inhibition stall de novo peptidoglycan synthesis at this early step and cause cell lysis in rapidly dividing bacteria
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