title: Staphylococcus aureus formyl-methionyl transferase mutants demonstrate reduced virulence factor production and pathogenicity.
abstract: Inhibitors of peptide deformylase (PDF) represent a new class of antibacterial agents with a novel mechanism of action. Mutations that inactivate formyl methionyl transferase (FMT), the enzyme that formylates initiator methionyl-tRNA, lead to an alternative initiation of protein synthesis that does not require deformylation and are the predominant cause of resistance to PDF inhibitors in Staphylococcus aureus. Here, we report that loss-of-function mutations in FMT impart pleiotropic effects that include a reduced growth rate, a nonhemolytic phenotype, and a drastic reduction in production of multiple extracellular proteins, including key virulence factors, such as α-hemolysin and Panton-Valentine leukocidin (PVL), that have been associated with S. aureus pathogenicity. Consequently, S. aureus FMT mutants are greatly attenuated in neutropenic and nonneutropenic murine pyelonephritis infection models and show very high survival rates compared with wild-type S. aureus. These newly discovered effects on extracellular virulence factor production demonstrate that FMT-null mutants have a more severe fitness cost than previously anticipated, leading to a substantial loss of pathogenicity and a restricted ability to produce an invasive infection.
authors.affiliation: Antibacterial Discovery Performance Unit, Infectious Diseases Therapeutic Area, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Lewandowski
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Huang
authors.forename: Frank
authors.initials: F
authors.lastname: Fan
authors.forename: Shannon
authors.initials: S
authors.lastname: Rogers
authors.forename: Daniel
authors.initials: D
authors.lastname: Gentry
authors.forename: Reannon
authors.initials: R
authors.lastname: Holland
authors.forename: Peter
authors.initials: P
authors.lastname: Demarsh
authors.forename: Kelly
authors.initials: K
authors.lastname: Aubart
authors.forename: Magdalena
authors.initials: M
authors.lastname: Zalacain
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001427:Bacterial Toxins / Q000096:biosynthesis / Q000235:genetics; D024881:Drug Resistance, Bacterial / Q000235:genetics*; D005098:Exotoxins / Q000096:biosynthesis / Q000235:genetics; D006460:Hemolysin Proteins / Q000096:biosynthesis / Q000235:genetics; D019877:Hydroxymethyl and Formyl Transferases / Q000235:genetics*; D007956:Leukocidins / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D008826:Microbial Sensitivity Tests; D011704:Pyelonephritis / Q000382:microbiology; D013203:Staphylococcal Infections; D013211:Staphylococcus aureus / Q000201:enzymology* / Q000235:genetics* / Q000472:pathogenicity; D037521:Virulence Factors
chemical_list: D000900:Anti-Bacterial Agents; D001427:Bacterial Toxins; D005098:Exotoxins; D006460:Hemolysin Proteins; D007956:Leukocidins; C078284:Panton-Valentine leukocidin; D037521:Virulence Factors; C021091:staphylococcal alpha-toxin; D019877:Hydroxymethyl and Formyl Transferases; C021561:methionyl-tRNA formyltransferase; D000581:Amidohydrolases; C084507:peptide deformylase