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

Antimicrob Agents Chemother. 2015 May 26. pii: AAC.00484-15. [Epub ahead of print]

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

Min S1, Ingraham K2, Huang J2, McCloskey L2, Rilling S2, Windau A3, Pizzollo J2, Butler D2, Aubart K2, Miller LA2, Zalacain M2, Holmes DJ2, O'Dwyer K2.

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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 causing 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 these mutations are associated with a severe in vitro and/or in vivo fitness cost. The overall FoR to GSK1322322 was very low in Haemophilus influenzae with only one PDF mutant 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 only isolated from six of 21 strains tested and an additional 10 strains did not yield colonies on GSK1322322-containing plates. Most of the PDF mutants characterized from these three organisms (35/37), carried mutations in residues at or in close proximity to one of three highly conserved motifs, which are part of the active site of the PDF protein, with 30 of the 35 mutations occurring at position V71 (S. pneumoniae numbering system).

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PMID: 26014938 [PubMed - as supplied by publisher]