Bacterial Switch Discovery Could Lead to New Anti-Infectives

Researchers at the University of California, Santa Barbara, have found a way to disarm microbial pathogens with the discovery of a molecular "cloaking device," effectively stopping pathogens in their tracks. The findings, published in the May 7 issue of Science, will be applied toward the development of a new generation of vaccines and antibiotics, according to the researchers.

Michael J. Mahan, associate professor of biology at UCSB, believes he has identified a "master switch" that controls the production of many of the weapons used by bacteria to invade cells. When Mahan disables the switch, bacteria are prevented from causing disease.

The master switch is the same within many pathogenic bacteria, including Vibrio cholerae (cholera), Yersinia (plague), Salmonella (typhoid fever), and Shigella (dysentery), and may apply to the treatment of these bacterial infections as well as others that are a major cause of death of AIDS and cancer patients. Unbelievably, microbial infections are the leading cause of death worldwide, responsible for nearly three times as many deaths as cancer.

Mahan's discovery will eventually aid in the fight against newly emerging, drug resistant pathogens. "When it comes to bacterial disease, the wake-up call has been sounded," Mahan warned last year at a UCSB award ceremony at which he was honored. "Our microbial defenses are crumbling as superior pathogens have emerged that can no longer be controlled by available antibiotics. Many of these bacteria that were once merely a nuisance have recently evolved into efficient killing machines. More than 30 new diseases have emerged within the last 20 years."

Mahan studies Salmonella, a rod-shaped bacteria that causes food poisoning in 4 million people in the U.S. every year. There are 2,500 different strains of Salmonella, and they are responsible for diseases ranging from food and blood poisoning to typhoid fever. Young children are the most vulnerable, with infants being 15 times as susceptible as adults.

The Science paper describes the results of using a novel approach to identify genes in bacteria that come alive when they infect mice, but are "cloaked" in the petri dish. Mahan compares the bacteria to a Trojan horse to describe the way they hide their destructive weapons until they are inside a cell. "You can't fight what you can't see," he said.

But Mahan has discovered a way to get the bacteria to reveal itself fully to the immune system, to show its hand. "Bacteria are great poker players," he said. "But no matter how good a poker player you are, if you lay your cards down, you're dead."

Mahan's new mutated strain of Salmonella, with the master switch on, now shows all its "cards"—its tricks for getting past the gut and into organs and tissues. "This has two important consequences," Mahan said, "the bacteria are completely disabled in their ability to cause disease, and these crippled bacteria work as a vaccine since they stimulate immune defenses to defend against subsequent infections."

Vaccines and antibiotics developed out of this discovery are expected to provide a major boon to human health worldwide, particularly in countries where many people die from bacterial infections. While application to human vaccines and antibiotics may be down the road a few years, Mahan sees significant impact on human health happening very soon—through the food supply. It might be possible, for example, to vaccinate chickens and cows to develop Salmonella-free poultry and E. coli-free beef. Such vaccines are sorely needed as the level of contamination in the food supply is expected to worsen due to large-scale animal processing and distribution practices, according to Mahan.

Why Conventional Bacteriology Fails
Identification of microbial virulence genes has been hampered by the fact that bacteria hide their cellular invasion plans until specific host signals are detected. Since the complex environment of animal tissues can not be duplicated in the laboratory, developing anto-infective drug strategies are difficult. Some of these limitations can be overcome by methods developed by Mahan, termed IVET (in vivo expression technology), which uses the animal as a selective medium to force bacteria to reveal their weapons (virulence genes) even though their function or mechanism of expression is unknown. Mahan hopes this unique class of virulence factors will lead to the development of new forms of treatment and prevention of infectious disease.

Using the IVET approach, Mahan has identified more than 200 Salmonella genes that are highly expressed in animal tissues compared to their poor expression on laboratory media. Many of these virulence genes are not shared with other pathogens, and thus define unique functions that allow Salmonella to attach to, invade, and replicate within the nutrient limiting conditions of the host. Mahan's ultimate goal is to examine the function and regulation of these virulence genes, with an emphasis on their contributions to Salmonella pathogenicity. In addition to defining the mechanisms by which bacterial pathogens cause disease, the applications of this research range from drug and vaccine design to the development of molecular probes for the rapid and sensitive detection of infectious organisms.

For more information: Michael Mahan, Professor, Dept. of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, CA 93106. Tel: 805-893-7160 (office); 805-893-3727 (lab). Email: mahan@lifesci.ucsb.edu.

By Angelo DePalma