Frequency of Spontaneous Resistance to Peptide Deformylase Inhibitor GSK1322322 in Haemophilus influenzae,
Sharon Min1, Karen Ingraham2, Jianzhong Huang2
1Antibacterial Discovery Performance Unit, Infectious Disease Therapeutic Area, GlaxoSmithKline, Collegeville, Pennsylvania, USA sharon.b.min@gsk.com.
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).
Insights
Resistance to the novel antibacterial GSK1322322 emerged frequently in Staphylococcus aureus and Streptococcus pyogenes via formyl-methionyl transferase (FMT) mutations, but with significant fitness costs. Resistance in Streptococcus pneumoniae was less frequent and also associated with fitness deficits.
Area of Science:
- Microbiology
- Antimicrobial Resistance
- Drug Discovery
Background:
- Multidrug-resistant bacteria pose a significant threat to public health, necessitating novel antimicrobial agents.
- Peptide deformylase (PDF) inhibitors, like GSK1322322, represent a promising class of antibacterials with demonstrated clinical potential.
- Understanding resistance mechanisms is crucial for the development and deployment of new antibiotics.
Purpose of the Study:
- To determine the frequency of resistance (FoR) to the novel PDF inhibitor GSK1322322 in key bacterial pathogens.
- To characterize the genetic basis and fitness implications of GSK1322322 resistance.
- To evaluate the potential for rapid resistance development to GSK1322322 in clinically relevant bacteria.
Main Methods:
- In vitro susceptibility testing of GSK1322322 against Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae, and Haemophilus influenzae.
- Isolation and sequencing of resistant mutants to identify genetic alterations.
- Assessment of in vitro and in vivo fitness costs associated with identified resistance mutations.
Main Results:
- High frequency of resistance to GSK1322322 was observed in S. aureus and S. pyogenes, primarily due to loss-of-function mutations in formyl-methionyl transferase (FMT).
- Resistance in S. pneumoniae occurred at a lower frequency via missense mutations, with mutations often localized to conserved active site motifs of PDF.
- Identified resistance mutations in all tested species were associated with substantial in vitro and/or in vivo fitness costs.
- Haemophilus influenzae exhibited a very low frequency of resistance to GSK1322322.
Conclusions:
- While resistance to GSK1322322 can emerge at a high frequency in certain pathogens like S. aureus and S. pyogenes, it is often linked to significant fitness disadvantages.
- The low frequency of resistance in H. influenzae and the fitness costs associated with resistance mutations suggest a potentially favorable resistance profile for GSK1322322.
- Further investigation into the clinical implications of these resistance mechanisms and fitness costs is warranted.
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