Defective lytic transglycosylase disrupts cell morphogenesis by hindering cell wall de-O-acetylation in Neisseria meningitidis

Allison Hillary Williams (1, 2) , Richard Wheeler (1) , Ala-Eddine Deghmane (3) , Ignacio Santecchia (1, 4) , Ryan E Schaub (5) , Samia Hicham (1) , Maryse Moya Nilges (6) , Christian Malosse (7) , Julia Chamot-Rooke (7) , Ahmed Haouz (8) , Joseph P Dillard (5) , William P Robins (9) , Muhamed-Kheir Taha (3) , Ivo Gomperts Boneca (1)

1 Biologie et Génétique de la Paroi bactérienne - Biology and Genetics of Bacterial Cell Wall
2 ITIC - Immunologie anti-tumorale et immunothérapie des cancers
3 Infections Bactériennes Invasives
4 UPD5 - Université Paris Descartes - Paris 5
5 Department of Medical Microbiology and Immunology
6 UTechS UBI - Plateforme BioImagerie Ultrastructurale – Ultrastructural BioImaging Platform
7 UTechS MSBio - Spectrométrie de Masse pour la Biologie – Mass Spectrometry for Biology
8 Cristallographie (Plateforme) - Crystallography (Platform)
9 HMS - Harvard Medical School [Boston]

Lytic transglycosylases (LT) are enzymes involved in peptidoglycan (PG) remodeling. However, their contribution to cell-wall-modifying complexes and their potential as antimicrobial drug targets remains unclear. Here, we determined a high-resolution structure of the LT, an outer membrane lipoprotein from Neisseria species with a disordered active site helix (alpha helix 30). We show that deletion of the conserved alpha-helix 30 interferes with the integrity of the cell wall, disrupts cell division, cell separation, and impairs the fitness of the human pathogen Neisseria meningitidis during infection. Additionally, deletion of alpha-helix 30 results in hyperacetylated PG, suggesting this LtgA variant affects the function of the PG de-O-acetylase (Ape 1). Our study revealed that Ape 1 requires LtgA for optimal function, demonstrating that LTs can modulate the activity of their protein-binding partner. We show that targeting specific domains in LTs can be lethal, which opens the possibility that LTs are useful drug-targets.

Keywords: E. coli; Lytic transglycosylase; Neisseria meningitidis; X-ray crystallography; cell division; cell separation; infectious disease; microbiology; peptidoglycan

Domains: Microbiology and Parasitology; Infectious diseases

Allison Hillary Williams, Richard Wheeler, Ala-Eddine Deghmane, Ignacio Santecchia, Ryan E Schaub, et al.. Defective lytic transglycosylase disrupts cell morphogenesis by hindering cell wall de-O-acetylation in Neisseria meningitidis. eLife, 2020, 9, pp.e51247. ⟨10.7554/eLife.51247⟩. ⟨pasteur-02947101⟩