Candidate Antibiotics Use Novel Attack Strategy

CHICAGO--Initial tests on a class of chemical compounds shows that they kill bacteria using a different weapon than any other antibiotics. If the compounds, unveiled here on 18 December at the American Society for Microbiology's Interscience Conference on Antimicrobial Agents and Chemotherapy, hold up under further testing, they could become a new weapon in the battle against antibiotic-resistant superbugs.

Most existing antibiotics kill bacteria using one of three strategies. The drugs may block microbes from assembling a cell wall, stop them from manufacturing new proteins, or prevent them from copying their DNA. But certain life-threatening bacteria, including those responsible for some cases of tuberculosis and pneumonia, have evolved defensive maneuvers to resist most available drugs. And efforts by pharmaceutical companies to find new antibiotics have yielded little: In the last 35 years, only one new class of antibiotic has been introduced into the clinic.

Hoping to add a second to the list, Roland Bürli and his colleagues at Genesoft Inc. of South San Francisco, California, turned to a well-studied class of synthetic compounds called heteroaromic polyamides, which can be custom-made by chemists to nestle into DNA's double helix, recognizing and disabling particular genes. Bürli speculated that by blocking key bacterial genes, their polyamides could kill microbes.

To test the compounds' power, his team screened 200 such compounds against three nasty bugs: methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecalis, and penicillin-resistant Streptococcus pneumoniae. The scientists found that four of the 200 compounds killed the bugs at relatively low doses, says Heinz Moser, chief technical officer for Genesoft. These four polyamides turned off essential genes that help the bacteria duplicate their genomes and make key proteins, according to results from another Genesoft team headed by James Ge.

The compounds "have the potential to be a real drug," says Jianshi Tao, director of molecular biology at Cubist Pharmaceuticals in Lexington, Massachusetts. But pharmacologist Steven Projan, who directs antibacterial research at Wyeth-Ayerst Research in Pearl River, New York, warns that polyamides could harm people if they bind to DNA in human cells as well as the bacteria's genes.

Related sites

Antimicrobial resistance fact sheet from the National Institute of Allergy and Infectious Diseases
Background on antibiotic resistance from the Food and Drug Administration
Genesoft corporate profile