Frequency of Spontaneous Resistance to Peptide Deformylase Inhibitor GSK1322322 in Haemophilus influenzae, Staphylococcus aureus, Streptococcus pyogenes, and Streptococcus pneumoniae

Abstract

ABSTRACTThe continuous emergence of multidrug-resistant pathogenic bacteria is compromising the successful treatment of serious microbial infections. GSK1322322, a novel peptide deformylase (PDF) inhibitor, shows goodin vitroantibacterial activity and has demonstrated safety and efficacy in human proof-of-concept clinical studies.In vitrostudies 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 inStaphylococcus aureus(4/4 strains) andStreptococcus pyogenes(4/4 strains) and via missense mutations inStreptococcus pneumoniae(6/21 strains), but the mutations were associated with severein vitroand/orin vivofitness costs. The overall FoR to GSK1322322 was very low inHaemophilus influenzae, with only one PDF mutant being identified in one of four strains. No target-based mutants were identified fromS. pyogenes, and only one or no PDF mutants were isolated in three of the fourS. aureusstrains studied. InS. 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 theS. pneumoniaenumbering system).