Sabotaging Bacterial Invaders

    By the end of most James Bond films, the super-suave secret agent has foiled some evil villain’s plot to inflict havoc on the universe. Armed with a myriad of snazzy gadgets and his infallible smarts, the spy outwits opponents skilled at resisting capture. Researchers at St. Jude Children’s Research Hospital know these types of villains all too well.

    For children with diseases like cancer, infection-causing bacteria are scarier than any movie monster. Cancer treatments often leave patients with weakened immune systems, so bacteria that may land an otherwise healthy person in bed for a few days can leave St. Jude patients desperately hanging onto their lives. To make matters worse, these microorganisms have proven adept at altering themselves to resist many antibacterial drugs, leading researchers to continually search for new modes of attack.

    Unlike 007, St. Jude scientists find that fighting catastrophic diseases is no task for a solo adventurer. Chemists, biologists and virologists collaborate through the hospital’s Small-Molecule Therapeutics Program to discover ways of sabotaging crucial systems in bacteria and other pathogens.

    Investigators from Infectious Diseases, Biochemistry, Structural Biology, Pathology, Molecular Pharmacology and Medicinal Chemistry are finding targets for new drugs so that children have the upper hand when fending off bacterial invaders.

    Serious stuff

    St. Jude researchers hope to combat this huge problem with small molecules that could derail the normal protein functions in pathogenic bacteria.

    “Finding the right type of chemical monkey wrench is crucial to overcoming drug-resistant bacteria,” says Charles Rock, PhD, of Infectious Diseases. “This is serious stuff. Bacteria have evolved mechanisms to defeat the available antibiotics. St. Jude is interested in tackling this problem because our kids have compromised immune systems, but this is really a national issue.”

    Rock and his colleagues are searching for molecules that can fit onto the surfaces of proteins like locks and keys. Once they infiltrate the bacteria, these undercover imposters modify the bacteria’s metabolism and bring their dreadful plans to a grinding halt.

    Stephen White, DPhil, chair of the St. Jude Structural Biology department, uses sophisticated software to understand how proteins are constructed and where small molecules could fit.

    “We’re looking for drugs to inhibit these protein molecules, and we’re looking at the method by which proteins interact with each other and with DNA so we can thwart them,” he says.

    Seasoned sleuth

    In his study of bacteria, Rock specifically looks for systems that are not duplicated in humans.

    “That way, if we knock the bacterial system out, it doesn’t affect us,” he says. “For example, penicillin knocks out one of the mechanisms whereby bacteria make their cell walls. Well, we don’t have those enzymes, so it doesn’t affect us and there are minimal side effects. The idea is to poison the bacteria, not poison the person.”

    With the patience of a seasoned sleuth, Rock has unraveled the cascades of biochemical reactions in bacteria that control the production of fatty acids.

    “When we began these studies 25 years ago, we were just trying to understand how things worked,” he says. “Over the years, I’ve been able to discover two key factors—bacteria must make fatty acids or they die, and this process is different from the human system.”

    While bacteria have evolved resistance to other antibacterial drugs, bacterial fatty acid synthesis is a new target that resistant organisms have not encountered. “So now we have something that’s absolutely essential for the life of the bacteria that is clearly different from what is in humans,” Rock says. “This is the fundamental target profile for developing drugs.”

    Artful swap

    Like Vincent van Gogh, Stephen White produces colorful, swirling 3-D images to give scientists blueprints of protein structures. But while the artist painted night skies and sunflowers, the structural biologist’s subject is much more serious—the bioterrorism agent anthrax.

    White is studying how slight mutations in the structure of a crucial anthrax bacterium enzyme called DHPS can make the pathogen resistant to antibiotics called sulfa drugs. If not for this resistance, sulfa drugs could be used to treat patients with infectious diseases. The antibiotic targets bacteria’s ability to produce folic acid, which is essential for making DNA. White and his team are studying new ways to disrupt this process in anthrax.

    “Bacteria have to make folate from scratch,” White says. “Humans get it from our diet. So it’s the perfect pathway. If we can kill the enzyme, the bacteria don’t make folate, don’t make DNA and die.”

    Sulfa drugs work by binding to DHPS, rendering it ineffective. Now that bacteria have found ways to work around this dead end, White’s team has discovered a potent inhibiting molecule called Manic, which fits onto the enzyme. Because most infectious bacteria use DHPS to make folate, the St. Jude findings hold promise for solving the problem of antibiotic resistance among microorganisms causing tuberculosis and pneumonia, as well as potential bioterrorism agents.

    Mission possible

    The next move is to translate these discoveries into drugs. To do that, St. Jude scientists are using powerful robots to search thousands of molecular compounds for ones that are both powerful and well-tolerated in the body. The hospital’s new Chemical Biology and Therapeutics program will dramatically boost this capability and provide an important new dimension to the hospital’s battle against childhood diseases.

    “This is really a story of how basic science can do good,” Rock says. “Treatments for catastrophic childhood diseases are not cash cows for big pharmaceutical companies, so our kids are basically an orphan population of patients. That’s why it’s important for St. Jude to think about these things. We are not going to get the therapeutics we need for these childhood diseases unless we go after these discoveries ourselves.”

    It doesn’t take James Bond to figure out why families count on St. Jude researchers to put away the bad guys and allow their children to set out on all the other adventures life has in store.

    Reprinted from summer 2005 Promise magazine

     

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