title: Blocking peptidoglycan recycling in Pseudomonas aeruginosa attenuates intrinsic resistance to fosfomycin.
abstract: Gram-negative bacteria recycle as much as half of their cell wall per generation. Here we show that interference with cell wall recycling in Pseudomonas aeruginosa strains results in four- to eight-fold increased susceptibility to the antibiotic fosfomycin, pushing the minimal inhibitory concentration for strains PA14 and PA01 to therapeutically appropriate values of 2-4 and 8-16 mg/L, respectively. A newly discovered metabolic pathway that connects cell wall recycling with peptidoglycan de novo biosynthesis is responsible for the high intrinsic resistance of P. aeruginosa to fosfomycin. The pathway comprises an anomeric cell wall amino sugar kinase (AmgK) and an uridylyl transferase (MurU), which together convert N-acetylmuramic acid (MurNAc) through MurNAc α-1-phosphate to uridine diphosphate (UDP)-MurNAc, thereby bypassing the fosfomycin-sensitive de novo synthesis of UDP-MurNAc. Thus, inhibition of peptidoglycan recycling can be applied as a new strategy for the combinatory therapy against multidrug-resistant P. aeruginosa strains.
authors.affiliation: Department of Biology, Interfaculty Institute of Microbiology and Infection Medicine Tübingen, University of Tübingen , Tübingen, Germany .
authors.forename: Marina
authors.initials: M
authors.lastname: Borisova
authors.forename: Jonathan
authors.initials: J
authors.lastname: Gisin
authors.forename: Christoph
authors.initials: C
authors.lastname: Mayer
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects; D002473:Cell Wall / Q000737:chemistry / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D024881:Drug Resistance, Bacterial / Q000187:drug effects*; D005578:Fosfomycin / Q000494:pharmacology*; D015870:Gene Expression; D053858:Metabolic Networks and Pathways; D008826:Microbial Sensitivity Tests; D009112:Muramic Acids / Q000378:metabolism; D009713:Nucleotidyltransferases / Q000235:genetics / Q000378:metabolism*; D051922:PII Nitrogen Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D010457:Peptidoglycan / Q000378:metabolism*; D010770:Phosphotransferases / Q000235:genetics / Q000378:metabolism*; D011550:Pseudomonas aeruginosa / Q000737:chemistry / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D014538:Uridine Diphosphate N-Acetylmuramic Acid / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D009112:Muramic Acids; D051922:PII Nitrogen Regulatory Proteins; D010457:Peptidoglycan; D014538:Uridine Diphosphate N-Acetylmuramic Acid; C031651:N-acetylmuramic acid; D005578:Fosfomycin; D010770:Phosphotransferases; D009713:Nucleotidyltransferases; C022515:regulatory protein uridylyltransferase