Peptide Deformylase Inhibitors - Blog

Overview

The dramatic rise in S. pneumoniae resistance to penicillin, macrolides, and other antimicrobials is concerning. While the fluoroquinolones currently enjoy a low level of bacterial resistance in the community, experts expect resistance against this class to increase as they are more widely used, thereby limiting future antibacterial options.

Consequently, there is considerable interest in the development of novel antimicrobials, such as peptide deformylase inhibitors, that have the potential to be active against pathogens resistant to currently available antimicrobials. Peptide deformylase is an enzyme involved in bacterial protein synthesis, and this target is highly conserved across bacterial species. Therefore, peptide deformylase inhibitors can potentially provide broad-spectrum activity. In addition, there appears to be little interaction with the human protein synthesis component; thus, the inhibitors are likely to have favorable selectivity to bacteria (and therefore safety in humans).

Peptide deformylase inhibitors are at an early stage of development but have generated much interest due to the need for novel, innovative antibacterials. Results from further trials will be needed to determine their efficacy and probable use in the future. Several companies, including Roche, are working on early-stage development of peptide deformylase inhibitors. Because of minimal available clinical trial information, Roche's compounds are not covered in detail.

Overall, this class represents a strategy that focuses on highly conserved bacterial targets while aiming to spare human protein synthesis, which may translate into useful options if resistance to current drugs continues to rise.

Table 1. Key features of peptide deformylase inhibitors
Aspect	Key details	Potential clinical implication
Primary target	Peptide deformylase enzyme involved in bacterial protein synthesis	Provides a novel mechanism distinct from penicillins, macrolides, and fluoroquinolones.
Conservation of target	Highly conserved across bacterial species	Potential for broad-spectrum antibacterial activity.
Selectivity for bacteria	Little interaction with human protein synthesis components	May offer favorable safety and tolerability in humans.
Development stage	Early-stage development with limited clinical trial data	Future studies are required to define their role in therapy.
Clinical need	Rising resistance in S. pneumoniae to multiple standard classes	Motivates investigation of new agents for community respiratory infections.

Mechanism of Action

Peptide deformylase is an essential bacterial metalloenzyme required for protein synthesis and thus represents a good target for antibacterial therapy. Peptide deformylase inhibitors act on the peptide deformylase enzyme, disrupting protein maturation and inhibiting protein synthesis. Protein synthesis in bacteria, under normal conditions, is initiated by the amino acid formyl-methionyl-tRNA. Consequently, all nascent polypeptides are synthesized with N-formyl-methionine at the N terminus. The formyl group is removed by peptide deformylase during elongation of the polypeptide chain. Deformylation is also a prerequisite for protein maturation. Peptide deformylase inhibitors act on the enzyme peptide deformylase to prevent deformylation of the growing peptide chain and thus inhibit protein synthesis.

By interfering at this early step in protein maturation, these agents may exert rapid bacteriostatic or bactericidal effects, depending on the organism and exposure, while leaving human protein synthesis largely unaffected.

BB-81384

Oscient Pharmaceuticals (formerly Genesoft/Genome Therapeutics), under license from Vernalis (formerly British Biotech), was developing a lead compound from a series of IV peptide deformylase inhibitors for the potential treatment of bacterial infections, and RTIs in particular. The agent was being explored as an IV therapy for potential application in acute exacerbations of chronic bronchitis. However, in March 2004, Genome Therapeutics stated this first-generation compound did not have the ideal spectrum of activity against common respiratory pathogens and that the company was exploring second-generation orally available peptide deformylase inhibitors with a greater potential to target the broader antibiotic market. Oscient Pharmaceuticals is currently investigating several preclinical oral peptide deformylase inhibitors for community-based RTIs. Several compounds have been identified as having attractive antibacterial properties, including good activity against H. influenzae.

BB-81384, a novel peptide deformylase inhibitor with good activity against S. pneumoniae in vitro, is the first compound of this class to be profiled for oral pharmacokinetics and has demonstrated oral anti-pneumococcal efficacy in mice. Pharmacokinetic studies in mice showed that the agent has good oral bioavailability. BB-81384 was a potent and selective inhibitor of peptide deformylase with an IC50 approximately 10 nM against most S. pneumoniae pathogens. In models of lung and thigh infection, BB-81384 reduced the bacterial load.

These findings suggest that BB-81384 can reach effective concentrations at sites of respiratory infection in animal models, but its eventual clinical usefulness will depend on human pharmacokinetics, safety, and comparative efficacy.

Table 2. Properties of BB-81384 described in preclinical studies
Property	Key data	Potential relevance
Class	Peptide deformylase inhibitor	Represents a first-in-class approach targeting protein maturation.
In vitro activity	Good activity against S. pneumoniae	Supports development for respiratory tract infections.
IC50 values	Approximately 10 nM against most S. pneumoniae pathogens	Indicates potent inhibition of the enzyme target in laboratory assays.
Oral pharmacokinetics	First compound of this class profiled for oral pharmacokinetics	Provides early evidence for possible oral dosing in humans.
Bioavailability	Good oral bioavailability in mice	Suggests that effective systemic levels may be achievable with oral therapy.
In vivo efficacy	Reduced bacterial load in lung and thigh infection models	Demonstrates proof of concept for activity in experimental infections.