29 September 2002 12:35 EST

by Apoorva Mandavilli

[caption and credit]

San Diego - The next new class of antibiotics will be inhibitors of an enzyme required for bacterial-protein synthesis, according to researchers here at the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy. The first clinical trial with an inhibitor of the enzyme peptide deformylase is scheduled to begin next month.

Peptide deformylase (PDF) is a member of a group called metalloenzymes, which require metal ions for their activity. Although between 3-5% of the bacterial genome codes for metalloenzymes, "at present, there are no antiobiotics that target metalloenzymes," said John Clements, project director for anti-infectives at British Biotech. "We see them very much as an underexploited resource."

In most bacteria that infect humans, PDF catalyzes the removal of a formyl group from the N-terminus of nascent proteins, a critical step in protein maturation. Blocking the iron-binding enzyme is therefore lethal to the bacteria, but does not affect humans. And PDF inhibitors have the potential to be both broad-spectrum as well as targeted therapies, Clements says.

To find targets for metalloenzyme inhibitors, the researchers searched genome databases based on similarity to known metalloenzymes and to metal-binding motifs. From the Bacillus subtilis genome, which has 4000 open reading frames, they found 150 potential targets, and validated their importance to the bacteria with knockout studies.

The first such inhibitor, BB83698 - a compound developed by British Biotech - will enter phase I clinical trials in October. This inhibitor, which interferes with the activity of the iron in PDF, was active against drug-resistant Streptococcus pneumoniae in two in vivo models of infection.

A second PDF inhibitor, from Versicor, Inc., has been effective against upper-respiratory pathogens such as S. pneumoniae, Moraxella catarrhalis, and Haemophilus influenzae(including drug-resistant strains) in preclinical studies.

Metalloenzyme inhibitors actually have multiple applications in the clinic. Inhibitors of angiotensin-converting enzyme (ACE) are used to treat congestive heart failure and hypertension; matrixmetalloproteinase inhibitors are in clinical development as cancer therapies; and urease inhibitors serve as adjuvant therapy for urinary-tract infections.

Inhibitors could also target agents such as anthrax toxin (the anthrax lethal factor is a zinc-dependent metalloproteinase), virulence factors such as proteases, and resistance determinants. Researchers have already identified inhibitors of urea amidohydrolase, the key virulence factor for Heliobacter pylori, and of Lpxc, an enzyme required for synthesis of the bacterial cell wall in gram-negative bacteria.

Although several companies are developing inhibitors of PDF and other metalloenzymes, they represent a "rather controversial target" for antibiotics, said Steve Pojan, director of antibacterials at Wyeth Research. "There are those of us who believe the only way they'll make money is if we charge for this session," added Pojan, who moderated the session on PDF inhibitors.

"The science that's been done has been superb," Pojan told BioMedNet News, but he has qualms about the inhibitors as a new class of antibiotics. Because the they target a single enzyme, resistance could emerge rapidly, he notes. Scientists also do not yet know what effect, if any, bacterial efflux pumps will have on the drugs.

Still, the inhibitors are one step ahead of ketolides, the only other new class of antibiotics on the horizon. Unlike ketolides, Pojan says, PDF inhibitors are active both against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus.

Picture caption and credit:
Peptide deformylase, image courtesy of Protein Data Bank.
PDB ID: 1BS4
A. Becker, I. Schlichting, W. Kabsch, D. Groche, S. Schultz, A. F. V. Wagner
Peptide Deformylase As Zn2+ Containing Form (Native) In Complex With Inhibitor Polyethylene Glycol
Nat.Struct.Biol. 5 pp. 1053 (1998)

Send us your comments for publication.

Sign up for BioMedNet News weekly email alerts.

Printer ready version
E-mail article to a friend

 

See also:
Antibiotic activity and characterization of BB-3497, a novel peptide deformylase inhibitor
Clements JM, Beckett RP, Brown A, et al.
Antimicrob Agents Chemother, 2001 Feb 45:563-70

Asymmetric synthesis of BB-3497 - a potent peptide deformylase inhibitor
Pratt LM, Beckett RP, Davies SJ, et al.
Bioorg Med Chem Lett, 2001 Oct 11:2585-8

Combinatorial chemistry in anti-infectives research
[Combinatorial chemistry]
Jac C.H.M. Wijkmans, R. Paul Beckett
Combinatorial Chemistry: A Supplement to Drug Discovery Today, 2002, 2002:2:126-132

The role of combichem in antibiotic discovery
[Review]
Joaquim Trias
Current Opinion in Microbiology, 2001, 4:5:520-525
 

Printer ready version
E-mail article to a friend