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New antibiotic target in Gram-negative bacteria: blocking the transport of virulence factors

By Maurice Steenhuis

New antibiotics are urgently needed, because antibiotic resistance continues to emerge and spread. One of the new classes of antibiotics, that is currently being investigated by many research groups, are the so-called anti-virulence drugs that block virulence factors. Virulence factors are bacterial components that disease-causing bacteria (pathogens) produce to be able to infect a host. For example, pathogens that enter the human intestines need to be able to stick to the intestinal epithelial layer and therefore use specialized virulence factors to adhere and colonize the intestine. AIMMS researchers Maurice Steenhuis and his colleagues aim to find new antibiotic like molecules that can block the action of these virulence factors. This new type of antibiotic disarms the pathogen of its virulence factors, making the pathogen harmless to the host.

In Gram-negative bacteria, such as Escherichia coli, most virulence factors are proteins that are transported from the inside of the bacterial cell to the outside. Bacteria use highly specialized secretion systems for transporting proteins. The so-called Type 5 secretion system or autotransporter secretion is most widely used by pathogens to transport proteins to the outside. To find molecules that block transport of virulence factors through the Type 5 secretion system Steenhuis and his colleagues designed the following assay. They grow E. coli bacteria that produce a virulence factor that is transported via the Type 5 secretion system. When a potential antibiotic like molecule blocks transport of the virulence factor the protein will accumulate in the bacterial cell. Bacteria do not like protein accumulation and become stressed. Steenhuis manipulated the bacteria in such a way that a bacterium becomes fluorescent when it is stressed. Using this assay many molecules were tested for their ability to make the bacteria fluorescent and several molecules that block the transport of virulence factors have been found. Currently, these molecules are further investigated and they may form a starting point for a new class of antibiotics.