title: Heteroresistance to fosfomycin is predominant in Streptococcus pneumoniae and depends on the murA1 gene.
abstract: Fosfomycin targets the first step of peptidoglycan biosynthesis in Streptococcus pneumoniae catalyzed by UDP-N-acetylglucosamine enolpyruvyltransferase (MurA1). We investigated whether heteroresistance to fosfomycin occurs in S. pneumoniae. We found that of 11 strains tested, all but 1 (Hungary(19A)) displayed heteroresistance and that deletion of murA1 abolished heteroresistance. Hungary(19A) differs from the other strains by a single amino acid substitution in MurA1 (Ala(364)Thr). To test whether this substitution is responsible for the lack of heteroresistance, it was introduced into strain D39. The heteroresistance phenotype of strain D39 was not changed. Furthermore, no relevant structural differences between the MurA1 crystal structures of heteroresistant strain D39 and nonheteroresistant strain Hungary(19A) were found. Our results reveal that heteroresistance to fosfomycin is the predominant phenotype of S. pneumoniae and that MurA1 is required for heteroresistance to fosfomycin but is not the only factor involved. The findings provide a caveat for any future use of fosfomycin in the treatment of pneumococcal infections.
authors.affiliation: Institute for Infectious Diseases, Faculty of Medicine, University of Bern, Bern, Switzerland.
authors.forename: Hansjürg
authors.initials: H
authors.lastname: Engel
authors.forename: Javier
authors.initials: J
authors.lastname: Gutiérrez-Fernández
authors.forename: Christine
authors.initials: C
authors.lastname: Flückiger
authors.forename: Martín
authors.initials: M
authors.lastname: Martínez-Ripoll
authors.forename: Kathrin
authors.initials: K
authors.lastname: Mühlemann
authors.forename: Juan A
authors.initials: JA
authors.lastname: Hermoso
authors.forename: Markus
authors.initials: M
authors.lastname: Hilty
authors.forename: Lucy J
authors.initials: LJ
authors.lastname: Hathaway
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D003460:Crystallization; D024881:Drug Resistance, Bacterial / Q000235:genetics*; D005578:Fosfomycin / Q000494:pharmacology*; D006801:Humans; D006814:Hungary; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D011008:Pneumococcal Infections / Q000188:drug therapy / Q000382:microbiology; D017422:Sequence Analysis, DNA; D013296:Streptococcus pneumoniae / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics
chemical_list: D000900:Anti-Bacterial Agents; D005578:Fosfomycin; D019883:Alkyl and Aryl Transferases; C022566:UDP-N-acetylglucosamine 1-carboxyvinyltransferase