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2-for-1 bacterial virulence factor revealed

We’ve all seen the headlines. “Man found to be shedding virulent strain of polio”; “Virulent flu strain in Europe hits the economy”; “Most virulent strain of E. coli ever seen contains DNA sequences from plague bacteria.”

To most of us “virulent” means “aggressive,” or just plain “bad,” but to a microbiologist it has a more specific meaning. Virulent strains of bacteria are ones that produce “virulence factors,” small molecules and proteins that convert a benign bacterium into a pathogen.

They make the difference between E. coli that are helpful members of our gut microbiome and the E. coli O157:H7 responsible for the Jack-in-the-Box outbreak.

Virulence factors allow bacteria to evade the human immune system, to infect tissues and cells and to establish a foothold within the body. Without them, bacteria would be rapidly cleared by the immune system and unable to establish an infection.

Tim Wencewicz, PhD, assistant professor of chemistry in Arts & Sciences at Washington University in St. Louis, thinks we should be looking for agents that block virulence factors rather than continuing to search for ones to kill bacteria outright. In his vision, antivirulence antibiotics would replace failing bactericidal ones.

“Do we have to find molecules that kill bacteria to fight bacterial infections?,” he asks. “Is that really what we have to do?”

Traditional antibiotics carry with them the seeds of their own destruction, he said. The megadoses of broad spectrum antibiotics often given to patients in clinical medicine apply tremendous selective pressure to bacterial communities, creating rich opportunities for resistant strains by eliminating all susceptible ones.

“Antivirulence antibiotics would apply much less selective pressure,” Wencewicz said. “If you treat bacteria in a test tube with an antivirulence antibiotic, the bacteria will grow as if there is no antibiotic there. But if you treat bacteria in the human body, bacterial growth will be suppressed. The antivirulence antibiotic behaves like a traditional bacteriostatic antibiotic, suppressing pathogen’s growth until the immune system has time to recognize and clear it.

“We could give anti-virulence antibiotics to people with healthy immune systems, who would be able to clear infections with this assistance,” he said, “and traditional antibiotics combined with antivirulence therapies to people with compromised immune systems, who really need them.”

In the online issue of the February issue of the ACS journal Infectious Diseases, Wencewicz describes one possible drug target: an iron-seeking molecule secreted by the bacterium Acinetobacter baumannii. Now that the complex biochemistry of this virulence factor is better understood, he plans to start looking for agents that block its synthesis or activity.