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Jul 1, 2010 (Vol. 30, No. 13)

Resistant Bugs Necessitate Tougher Tactics

A Handful of Companies Report Progress in Developing Next-Generation Antibacterial Agents

  • Multidrug-resistant bacteria pose a significant threat to global health. In 2004, the World Health Organization provided a list of the top 10 diseases for which there will be inadequate therapies in the near future. Infection by resistant bacteria topped the list, ahead of cancer and diabetes. In the U.S., methicillin-resistant Staphylococcus aureus alone annually infects more than 94,000 people and kills nearly 19,000—more deaths than from homicides, HIV/AIDS, Parkinson disease, or emphysema.

    Additionally, resistant bacteria create an immense economic burden. One study suggested that such infections cost a staggering $21–34 billion in the U.S. alone. Although the need is rapidly increasing, there are growing concerns that the pipeline is withering away. A panel discussion at the “BIO International Convention” tackled these challenging questions, reviewed the current crisis, and discussed new solutions to create novel strategies for next-generation antibiotic agents.

    “A perfect storm is closing in on antibiotic resistance,” suggested Michael Kurilla, M.D., Ph.D., director of the office of biodefense research affairs of the NIAID. “Although few companies are pursuing it, there is a large and growing unmet need for new antibiotics in the pipeline for drug discovery. There are many challenges that the industry faces, including regulatory uncertainties and market pressures. Another vexing issue is the ability of microorganisms to become resistant even to newly developed drugs.” 

    There are many types of emerging resistant bacterial strains. Some of the most common ones are gram-negative organisms such as Acinobacter, Pseudomonas, and others with extended spectrum beta-lactamases. Oral agents are needed for gram-positive strains as well. “Deciding which clinical indications to focus on is largely a matter of technical feasibility and market attractiveness.”

    “While over ten years ago, there were numerous companies pursuing antibiotic drug discovery, today that number has shrunk to a handful. Help needs to come from several fronts. The FDA can assist by providing improved guidelines to help prioritize interests. Second, science must focus on and make strides especially in understanding serious gram-negative infections. Additionally, the market itself must become reasonable for development. Perhaps biotechnology can step up to provide new solutions and new approaches.”

  • Synthesis Strategy

    Click Image To Enlarge +
    Tetraphase Pharmaceuticals prepares novel analogs with a convergent synthesis process that uses two advanced precursors, which allow modifications to be introduced at virtually any position on the resulting tetracyclic core. This diversity provides an enriched set of antibacterials with novel pharmacological properties.

    Joyce A. Sutcliffe, Ph.D., senior vp biology at Tetraphase Pharmaceuticals, described the company’s approach for generating a new class of highly potent and safe antibiotics via a novel synthesis strategy.

    “Making only slight synthetic changes in current drug scaffolds can result in big differences in terms of pharmacological properties. Our company is focusing on tetracyclines, which are historically, among the most successful classes of broad-spectrum antibiotics. They are also one of the most difficult to work with—only one new compound in this class has been approved in more than 30 years, largely because of chemical-modification constraints.” 

    “Our process was developed by Andrew Myers, Ph.D., chair of the department of chemistry and chemical biology at Harvard University. After 10 years of research, he developed a novel and completely synthetic approach to generate new tetracycline drugs and derivatives. In the past, chemically modified tetracycline analogs have been produced using solely semisynthetic or chemical transformation of isolated natural products. This severely limited the range of new drug candidates.

    “Our core technology can modify tetracycline at any position. Our approach has provided us with a platform from which multiple complementary products have been generated, allowing us to identify potent compounds with the best spectrum and pharmacokinetic properties to meet medical needs.”

    Tetraphase currently has one candidate, TP-434, that has completed Phase I trials;  it is anticipated that it will enter Phase II studies later this year. Tetraphase has two additional IV/oral candidates for gram-negative infections or community-acquired bacterial pneumonia that are scheduled to enter Phase I trials in 2011.

    “Our lead candidate TP-434 is effective against gram-positive, gram-negative, and anaerobic pathogens, except Pseudomonas,” Dr. Sutcliffe reported. “Because of its broad spectrum, it is expected to be utilized for complicated intra-abdominal infections, hospital-acquired pneumonia, complicated urinary tract infections, and acute bacterial skin and skin structure infections.” 

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