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January 18, 2016

Discovery of a Dual-Natured Virulence Factor Could Open Door to New Antimicrobial Drugs

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    A rainbow of samples created by different concentrations of siderophores, molecules secreted by bacteria to steal iron from a host during an infection. [Shangwen Luo/ University of Illinois at Chicago]

    The speed at which microbial pathogens are developing resistance to our current arsenal of antibiotics is not just staggeringly fast; it's positively frightening.

    Over the past several years scientists have been united in a common objective: to develop compounds that can circumvent drug-resistant bacteria, as well as slow the rate at which microbes develop resistant mechanisms. To that end, researchers have begun to observe various bacterial mechanisms that slow proliferation rates and allow the immune system enough time to deal with the infection.

    Researchers at Washington University in St. Louis are looking for agents that block virulence factors—molecules that allow bacteria to evade the immune system, infect tissues and cells, and establish a foothold in the body—rather than continuing to search for compounds to kill bacteria outright.  

    "Do we have to find molecules that kill bacteria to fight bacterial infections?" asked senior study author Tim Wencewicz, Ph.D., assistant professor of chemistry at Washington University in St. Louis. "Is that really what we have to do?"

    Using our current pool of antibiotics is a double-edged sword; while many are often effective at killing bacteria, they also exert a tremendous amount of selective pressure on bacterial communities, forcing the exponential rise in drug resistance.

    "Antivirulence antibiotics would apply much less selective pressure," Dr. Wencewicz explained. "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 growth until the immune system has time to recognize and clear it.”

    "We could give antivirulence antibiotics to people with healthy immune systems who would be able to clear infections with this assistance," Dr. Wencewicz continued, "and traditional antibiotics combined with antivirulence therapies to people with compromised immune systems who really need them."

    In a newly published study, Dr. Wencewicz and his team describe a possible novel drug target: an iron-seeking molecule secreted by the bacterium Acinetobacter baumannii—a particularly virulent and pathogenic bacterial strain that emerged on the battlefield during the wars in the Middle East. The WashU investigators believe that compounds that block this virulence factor’s activity or synthesis could be an effective treatment.

    The findings from this study were published recently in Infectious Diseases through an article entitled “Acinetobactin Isomerization Enables Adaptive Iron Acquisition in Acinetobacter baumannii through pH-Triggered Siderophore Swapping.”

    One class of virulence factors common to many pathogens is siderophores, small molecules whose job is to seek out iron in the environment, wrap around it, and bring it back to the bacterial cell.

    “When you get an infection, your body's first response is to starve out the invader. You hide all your nutrients: you flush your amino acids into your kidneys and drain all nutrient supplies in the blood," Dr. Wencewicz said.

    This is an especially effective tactic in the case of iron because it is in such short supply within the human body—roughly only one free molecule per 1.6 liters of blood. 

    "Bacteria have to fight this huge concentration gradient in order to grab enough iron to proliferate," Dr. Wenecewics added.

    While A. baumannii makes three siderophores that work in concert to create a gradient of iron chelation that feeds the metal back to the bacterial cell, the researchers focused their study on a siderophore found in every single clinical isolate of A. baumannii: acetintobactin.

    Previous research on the fish pathogen Vibrio allowed the scientists to understand that this microbe made a similar compound, called pre-anguibactin. However, pre-anguibactin is locked in the "pre" form and does not isomerize, so in this case it seems the "pre" form is a functional siderophore. The researchers then began to speculate on which of the two forms of acinetobactin was a real siderophore: the pre-acinetobactin, the acinetobactin—or both. 

    What the scientists found was that A. baumannii was successful over a wide pH range because its pre-acinetobacin can isomerize.

    "We discovered that pre-acinetobacin is stable at a slightly acidic pH of 5, but at the more basic pH of 8 it rapidly isomerizes to acinetobactin," Wencewicz said. "Suppose A. baumannii has established itself in a slightly acidic open wound but depletes the resources there. To gain access to more nutrients it enters the bloodstream, but the pH of blood is 7.4 not 5. When the pH of the bacterium's environment changes, the pre-acinetobactin converts to acinetobactin, which performs better at the new pH."

    In short, A. baumannii has evolved a two-for-one siderophore whose conversion from one form to another is triggered by a change in pH.

    "Now that we know how this siderophore works, we can properly frame techniques to block it," Wencewicz added. "For example, we might attach something bulky to the siderophore so that when it docks on the bacterium’s receptor, it plugs it, preventing the siderophore from ferrying the iron inside."

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