CiQUS researchers develop a compound that reduces bacterial virulence

In a research article recently published by the prestigious American journal, Journal of American Chemical Society (J. Am. Chem. Soc. 2015, 137, 9333-9343 (link is external)), researchers from Concepción González-Bello´s group in the CiQUS, and with the participation of researchers from the University of Newcastle in UK, the A Coruña´s University Hospital Complex (CHUAC) and the National Centre of Biotechnology (CNB) in Madrid, describe the development of a new compound that is able to put the brakes on to bacterial virulence, specially Gram-negative bacteria – the “hospital nightmare”.

Bacteria apply the saying "there is strength in numbers". Thus, in isolation or in small groups they are not a problem for the body's defenses, but in a "team", when the "quorum" is reached, they become, in many cases, a nightmare due to the produced infection. This phenomenon, which is specially developed in Gram-negative bacteria, the most dangerous and "virulent" ones, occurs thanks that bacteria are able to communicate with each other to reach the quorum and therefore to achieve their objective, spread where infected.

This type of bacterium “vents its rage on” patients in intensive care units because their reduced immune system. As a consequence, what would be a manageable infection with the numerous antibiotics available or even with their own defenses becomes another health problem to overcome.

CiQUS researchers have developed a compound (an inhibitor) that blocks the action of an enzyme involved in bacterial virulence. It does not kill the bacteria, but it “reduces its virulence” and as a consequence, they could be eliminated by the immune system. It is a strategy that in recent years is being investigated by several research groups worldwide as a promising alternative to antibiotics. The novelty of the research conducted by the González Bello´s research group lies in the mode of action of the compound and the therapeutic target, the type 1 dehydroquinase, which to date had not been addressed.

The researchers show that this enzyme is a good target for treating infections caused by very important, such as pathogenic bacteria Staphylococcus aureus, a major cause of hospital infections, Escherichia coli, whose virulent strains can cause serious intestinal and extra-intestinal infections and Salmonella typhi, the bacteria responsible for typhoid fever. Moreover, since this enzyme is absent in mammals, a specific action on the bacteria is achieved and not on other human proteins, which is key to avoid adverse reactions.

The compound, which was developed by CiQUS researchers, is an improved version of another that has been recently been discovered by the same group and published earlier this year as a cover in the journal Organic Biomolecular Chemistry (Org. Biomol. Chem. 2015, 13, 706-716 (link is external)). The new inhibitor, which is similar to glucose, is safer and more potent than the previous one. The compound “deceives” the bacterium because it is similar to that used naturally reacting specifically with the active center of the enzyme and thereby blocking their behavior. In the article, the researchers studied in detail this mode of action and manage to solve the crystal structure of the enzyme modified by the inhibitor. This information is very relevant for the future design of new more potent inhibitors as researchers continue actively working. These promising results are part of one of the objectives of a research project funded by the MINECO within Challenges by the Society program in the Health section.

Links:

http://pubs.acs.org/doi/abs/10.1021/jacs.5b04080?journalCode=jacsat (link is external)

http://pubs.rsc.org/en/content/articlelanding/2014/ob/c4ob01782j#!divAbstract (link is external)