title: Penicillin resistance compromises Nod1-dependent proinflammatory activity and virulence fitness of neisseria meningitidis.
abstract: Neisseria meningitidis is a life-threatening human bacterial pathogen responsible for pneumonia, sepsis, and meningitis. Meningococcal strains with reduced susceptibility to penicillin G (Pen(I)) carry a mutated penicillin-binding protein (PBP2) resulting in a modified peptidoglycan structure. Despite their antibiotic resistance, Pen(I) strains have failed to expand clonally. We analyzed the biological consequences of PBP2 alteration among clinical meningococcal strains and found that peptidoglycan modifications of the Pen(I) strain resulted in diminished in vitro Nod1-dependent proinflammatory activity. In an influenza virus-meningococcal sequential mouse model mimicking human disease, wild-type meningococci induced a Nod1-dependent inflammatory response, colonizing the lungs and surviving in the blood. In contrast, isogenic Pen(I) strains were attenuated for such response and were out-competed by meningococci sensitive to penicillin G. Our results suggest that antibiotic resistance imposes a cost to the success of the pathogen and may potentially explain the lack of clonal expansion of Pen(I) strains.
authors.affiliation: Institut Pasteur, Unité des Neisseria, 25-28 rue du Dr. Roux, Paris 75724, France.
authors.forename: Maria Leticia
authors.initials: ML
authors.lastname: Zarantonelli
authors.forename: Anna
authors.initials: A
authors.lastname: Skoczynska
authors.forename: Aude
authors.initials: A
authors.lastname: Antignac
authors.forename: Meriem
authors.initials: M
authors.lastname: El Ghachi
authors.forename: Ala-Eddine
authors.initials: AE
authors.lastname: Deghmane
authors.forename: Marek
authors.initials: M
authors.lastname: Szatanik
authors.forename: Céline
authors.initials: C
authors.lastname: Mulet
authors.forename: Catherine
authors.initials: C
authors.lastname: Werts
authors.forename: Lucie
authors.initials: L
authors.lastname: Peduto
authors.forename: Martine Fanton
authors.initials: MF
authors.lastname: d'Andon
authors.forename: Françoise
authors.initials: F
authors.lastname: Thouron
authors.forename: Faridabano
authors.initials: F
authors.lastname: Nato
authors.forename: Lionel
authors.initials: L
authors.lastname: Lebourhis
authors.forename: Dana J
authors.initials: DJ
authors.lastname: Philpott
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Girardin
authors.forename: Francina Langa
authors.initials: FL
authors.lastname: Vives
authors.forename: Philippe
authors.initials: P
authors.lastname: Sansonetti
authors.forename: Gérard
authors.initials: G
authors.lastname: Eberl
authors.forename: Thierry
authors.initials: T
authors.lastname: Pedron
authors.forename: Muhamed-Kheir
authors.initials: MK
authors.lastname: Taha
authors.forename: Ivo G
authors.initials: IG
authors.lastname: Boneca
mesh_terms: D000818:Animals; D002473:Cell Wall / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D051379:Mice; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D009345:Neisseria meningitidis / Q000187:drug effects / Q000276:immunology / Q000472:pathogenicity*; D053474:Nod1 Signaling Adaptor Protein / Q000276:immunology*; D010403:Penicillin Resistance; D046915:Penicillin-Binding Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D050505:Mutant Proteins; D053474:Nod1 Signaling Adaptor Protein; C507873:Nod1 protein, mouse; D046915:Penicillin-Binding Proteins