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Novel Technology that Re-Sensitizes Resistant Bacteria to Last-Hope Antibiotic Is Commercialized

By Loralee Nolletti

Columbia and Rockefeller universities have signed an agreement to commercialize an engineered molecule used in a process that re-sensitizes resistant bacteria to vancomycin, considered the treatment of last resort for Gram-positive bacteria.

Antibiotic resistance has become an alarming problem with more than 17 million people worldwide dying each year from infections caused by Gram-positive bacteria, acquired in hospital and community settings.

Treating hospital-acquired infections presents a particular challenge. Mostly, the bacteria that cause these infections remain sensitive to vancomycin. However, over the past several years, there has been an increase in vancomycin-resistant enterococci, typically non-disease causing bacteria that inhabit the intestine. When these bacteria become pathogenic, they can become deadly.

Although the development of new antibiotics is a significant approach to the problem, another approach is to identify and block the mechanism through which resistance occurs. A team of researchers from Columbia and Rockefeller universities, William Clark Still, emeritus professor of chemistry at Columbia, Gabriela Chiosis, formerly of Columbia and currently at Sloan-Kettering, and Ivo G. Boneca, formerly of Rockefeller and currently at Institut Pasteur, identified this novel approach, and the two institutions are joint owners of this patent-pending technology.

The researchers' work, published in Science on Aug. 24, 2001, demonstrates that small engineered molecules with well-oriented nucleophile-electrophile assembly (a stable molecule where one chemical compound is giving electrons and the other receiving electrons) and complementary chirality (or compatible molecular structures) to the peptidoglycan termini can catalyze and selectively cleave the peptidoglycan precusor depsipeptide, a portion of the bacteria's cell wall. When used in conjunction with vancomycin, the molecules revitalize the antibiotic's efficacy against vancomycin resistant bacteria. In effect, the molecular process changes the configuration of the bacteria to allow vancomycin to inhibit cell wall synthesis.

Antibiotics like vancomycin attack cell wall synthesis in bacteria. When vancomycin works, it inhibits Gram-positive bacterial cell wall assembly by binding to the terminal D-Ala-D-Ala of peptidoglycan building blocks, a specifically configured chain of amino acids linked by peptide bonds. In resistant bacteria, the D-Ala-D-Ala changes to D-Ala-D-Lac, preventing the antibiotic from achieving its goal of inhibiting cell wall synthesis and, thus, diminishes vancomycin's affinity for the peptidoglyan layer.

"The patent could give Columbia ownership rights to a broad class of drugs to overcome resistance to certain antibiotics such as vancomycin," said Beth Kauderer, associate director of Science and Technology Ventures (S&TV), Columbia's technology transfer office, created to facilitate the transfer of scientific discovery and innovation to the marketplace. "Bacteria have been evolving to be resistant to even last-resort antibiotics, such as vancomycin, causing simple infections to become life-threatening. This invention provides an effective and innovative method for destroying resistant bacteria before they get uncontrollable."

The current molecule will require further development to bring it to the optimal level of efficacy necessary for the commercial market, according to Kauderer. Columbia can either look to license the technology to a pharmaceutical or large biotech company who will use the molecule to create a more optimized drug or the University can remain directly involved by partnering with a small drug development company to develop the technology further.

Published: Feb 22, 2002
Last modified:Sep 18, 2002


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