title: Frequency of Spontaneous Resistance to Peptide Deformylase Inhibitor GSK1322322 in Haemophilus influenzae, Staphylococcus aureus, Streptococcus pyogenes, and Streptococcus pneumoniae.
abstract: The continuous emergence of multidrug-resistant pathogenic bacteria is compromising the successful treatment of serious microbial infections. GSK1322322, a novel peptide deformylase (PDF) inhibitor, shows good in vitro antibacterial activity and has demonstrated safety and efficacy in human proof-of-concept clinical studies. In vitro studies were performed to determine the frequency of resistance (FoR) to this antimicrobial agent in major pathogens that cause respiratory tract and skin infections. Resistance to GSK1322322 occurred at high frequency through loss-of-function mutations in the formyl-methionyl transferase (FMT) protein in Staphylococcus aureus (4/4 strains) and Streptococcus pyogenes (4/4 strains) and via missense mutations in Streptococcus pneumoniae (6/21 strains), but the mutations were associated with severe in vitro and/or in vivo fitness costs. The overall FoR to GSK1322322 was very low in Haemophilus influenzae, with only one PDF mutant being identified in one of four strains. No target-based mutants were identified from S. pyogenes, and only one or no PDF mutants were isolated in three of the four S. aureus strains studied. In S. pneumoniae, PDF mutants were isolated from only six of 21 strains tested; an additional 10 strains did not yield colonies on GSK1322322-containing plates. Most of the PDF mutants characterized from those three organisms (35/37 mutants) carried mutations in residues at or in close proximity to one of three highly conserved motifs that are part of the active site of the PDF protein, with 30 of the 35 mutations occurring at position V71 (using the S. pneumoniae numbering system).
authors.affiliation: Antibacterial Discovery Performance Unit, Infectious Disease Therapeutic Area, GlaxoSmithKline, Collegeville, Pennsylvania, USA sharon.b.min@gsk.com.
authors.forename: Sharon
authors.initials: S
authors.lastname: Min
authors.affiliation: Antibacterial Discovery Performance Unit, Infectious Disease Therapeutic Area, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Ingraham
authors.affiliation: Antibacterial Discovery Performance Unit, Infectious Disease Therapeutic Area, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Huang
authors.affiliation: Antibacterial Discovery Performance Unit, Infectious Disease Therapeutic Area, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Lynn
authors.initials: L
authors.lastname: McCloskey
authors.affiliation: Antibacterial Discovery Performance Unit, Infectious Disease Therapeutic Area, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Rilling
authors.affiliation: Laboratory Specialists, Inc., Westlake, Ohio, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Windau
authors.affiliation: Antibacterial Discovery Performance Unit, Infectious Disease Therapeutic Area, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Pizzollo
authors.affiliation: Antibacterial Discovery Performance Unit, Infectious Disease Therapeutic Area, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Butler
authors.affiliation: Antibacterial Discovery Performance Unit, Infectious Disease Therapeutic Area, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Kelly
authors.initials: K
authors.lastname: Aubart
authors.affiliation: Antibacterial Discovery Performance Unit, Infectious Disease Therapeutic Area, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Linda A
authors.initials: LA
authors.lastname: Miller
authors.affiliation: Antibacterial Discovery Performance Unit, Infectious Disease Therapeutic Area, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Zalacain
authors.affiliation: Antibacterial Discovery Performance Unit, Infectious Disease Therapeutic Area, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Holmes
authors.affiliation: Antibacterial Discovery Performance Unit, Infectious Disease Therapeutic Area, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: O'Dwyer
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D006192:Haemophilus Infections / Q000188:drug therapy; D006193:Haemophilus influenzae / Q000187:drug effects*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests / Q000379:methods; D011008:Pneumococcal Infections / Q000188:drug therapy; D013203:Staphylococcal Infections / Q000188:drug therapy; D013211:Staphylococcus aureus / Q000187:drug effects*; D013296:Streptococcus pneumoniae / Q000187:drug effects*; D013297:Streptococcus pyogenes / Q000187:drug effects*
chemical_list: D000900:Anti-Bacterial Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; C583947:GSK1322322; D006877:Hydroxamic Acids; D000581:Amidohydrolases; C084507:peptide deformylase