Decorating old drugs to combat resistance

MADISON,Wis.—In a recent issue of the Journal of the American Chemical Society, researchers at the University of Wisconsin-Madison and Milwaukee's Medical College of Wisconsin described their efforts to bring new life to old antibiotics that are quickly being made obsolete by multidrug-resistant microbes (see Delaying the inevitable?). The technology—neoglycorandomization—involves the attachment of sugar and lipid groups to drugs to either help them find new metabolic targets within microbes or avoid the resistance pathways the microbes have evolved.

"Neoglycorandomization presents one of the first practical methods to broadly probe the sugar and lipid structure-activity relationships of lipoglycopeptide and glycopeptide antibiotics," says Dr. Jon Thorson, leader of the study and member of UWis's Division of Pharmaceutical Sciences. "Once the uniquely reactive 'handle' has been installed, natural or unnatural sugars—including 'lipid'-substituted sugars—can be efficiently attached in a single-pot reaction without the need for protecting groups or sugar activation—the two major limitations of existing chemical glycosylation methods."

In their latest effort, the researchers used their technique to generate a small library of vancomycin derivatives, testing the drug candidates against a series of vancomycin-resistant enterococci (VRE) strains. They quickly noted candidates with activity against the bacteria and in the best case, identified a derivative 40-fold more potent than vancomycin.

"Although many of the details remain to be elucidated, the lipid clearly influences the induction of antibiotic resistance, the ADME properties of lipoglycopeptides, and can even redirect the antibiotic to different biological targets," Thorson says. "Thus, lipid optimization has already played a major role in the development of second-generation lipoglycopeptide antibiotics."

The research comes at a time when the pharmaceutical industry is only just beginning to re-establish itself in the antibiotic market, having largely left the area to small biotechnology and drug companies for the past decade or so. According to Melissa Elder, a pharmaceutical analyst with Kalorama Information, increasing competition from generics and decreasing efficacy of first-generation drugs are significant components of the renewed interest.

"Developing new, low-resistant potential antibiotics are an attractive area of research for companies," she says. "These drugs tend to receive Fast Track approval quite regularly, and with the resistance issues current drugs are facing, there is a growing, recognized need. Companies such as Johnson & Johnson, Pfizer, and GlaxoSmithKline will likely be most interested in collaboration agreements with smaller development companies to help maintain leading positions in the antibiotic market."

In fact, despite revenue decreases in the antibacterials market in recent years, a Kalorama report released a few months ago suggests the market will see steady growth over the next few years and may actually surpass the $25 billion mark by 2010.

Neoglycorandomization is not limited to antibiotics, however. According to Thorson, the technology can be applied to a variety of therapeutic areas, regardless of whether a current drug is glycosylated.

"For example, neoglycorandomization of the cardiac glycoside digitoxin led to the discovery of analogues with remarkably improved anticancer properties but greatly diminished activity against the heart Na+/K+-ATPase—the digitoxin target and contributor to cardiotoxicity of such drugs," he says. "Neoglycorandomization of the non-glycosylated drug colchicine—a treatment for gout—led to the discovery of less toxic analogues that displayed uniquely improved synergy with classical anticancer agents such as taxol and other cytotoxic analogs that functioned via a mechanism fundamentally distinct from the parent drug."

The patent for the technology is owned by the Wisconsin Alumni Research Foundation (WARF) and has been exclusively licensed to local biotechnology company Centrose, which is "aggressively pursuing commercial applications" for the technology, according to company CEO James Prudent. Thorson helped found Centrose.

Meanwhile, Thorson's research group will continue to develop the technology, both as a tool unto itself and as a way of shining light on the functional roles of sugars attached to small molecules and drugs.