Mechanism Of Unusual Antibiotic | August 13, 2007 Issue - Vol. 85 Issue 33 | Chemical & Engineering News
Volume 85 Issue 33 | p. 13 | News of The Week
Issue Date: August 13, 2007

Mechanism Of Unusual Antibiotic

Picture of lactivicin bound to its target protein may aid fight against drug-resistant bacteria
Department: Science & Technology | Collection: Life Sciences
News Channels: Biological SCENE
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Phenoxyacetyl-lactivicin (electron density shown in green) complexed with penicillin-binding protein
Credit: Nat. Chem. Biol. © 2007
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Phenoxyacetyl-lactivicin (electron density shown in green) complexed with penicillin-binding protein
Credit: Nat. Chem. Biol. © 2007

Crystal structures of a long-neglected antibiotic may provide a starting point for more effective drugs against bacteria resistant to antibiotics such as penicillin.

The antibiotic is lactivicin, and crystal structures of it bound to penicillin-binding protein (PBP) reveal how it interacts with its target. Lactivicin is unusual because it is the only known naturally occurring PBP inhibitor that doesn't contain a β-lactam (a four-membered cyclic amide), a structural feature that is key to the biological activity of the group of antibiotics that includes penicillin and cephalosporins.

Lactivicin was first discovered more than 20 years ago, but it has languished because of its poor potency. A European team led by Christopher J. Schofield at the University of Oxford and Andr??a Dessen at the Institute of Structural Biology, in Grenoble, France, hopes to revive interest in its analogs.

Many drug-resistant bacteria have mutations in their PBPs that allow them to evade β-lactams. Instead of a β-lactam ring, lactivicin and its derivatives contain separate cycloserine and γ-lactone (a five-membered cyclic ester) rings. This structural difference allows lactivicins to recognize and inhibit mutated PBPs from resistant bacteria.

Schofield, Dessen, and coworkers have now obtained crystal structures of lactivicin and a more potent analog, phenoxyacetyl-lactivicin, each complexed with the PBP from Streptococcus pneumoniae (Nat. Chem. Biol., DOI: 10.1038/nchembio.2007.21). In both complexes, both of the lactivicin rings are open, and the antibiotics covalently bond to a serine in the protein. The researchers were surprised by "how close in structure the resultant inhibitor complex was to the analogous complex formed by reaction with a β-lactam," Schofield says.

"The work is a beautiful example of how chemistry and structural biology can converge in finding answers to important biomedical problems," says Shahriar Mobashery, an antibiotic resistance expert at the University of Notre Dame. "The mechanism is novel, and it might stimulate further study in the system by others to exploit it fully."

Schofield hopes that the structure may inspire a renewed interest in this long-neglected family of antibiotics. "This is by no means a solution to the problem of antibiotic resistance," he says. But "the structure may provide ideas to develop compounds that don't suffer from the same problems of resistance."

 
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