The prestigious American journal, ‘Journal of Medicinal Chemistry‘, which is focused on the latest advances in drug discovery, has recently highlighted a recent work (link is external) from the Concepción González Bello´s research group in the CiQUS, with the participation of researchers from the University of Newcastle in UK and the Hospital Universitario A Coruña (CHUAC), in which they have developed new compounds to face with the stomach infections caused by the pathogenic bacteria Helicobacter pylori that act by a novel mechanism of action.
This Gram-negative bacterium, a widespread bacterium as more than half of the population are infected (does not imply that they will develop the disease in all cases) is responsible for chronic gastritis and is associated with the gastroduodenal ulcers. In some cases, people infected with this pathogen are also at risk to suffer from stomach cancer. Consequently, it has been classified by the World Health Organization (WHO) as carcinogenic agent type I.
The treatment of H. pylori infections is complex because the bacterium is stick as “glue” to the gastric mucosa and the pH gradient, which naturally exists between the lumen gastric (pH 2) and gastric mucosa (pH 7), is not the “ideal” for antibiotics. The typical therapy is the treatment, for about 10 days, with a proton-pump inhibitor (such as omeprazole, pantoprazole or lansoprazole), and antibiotics (clarithromycin, amoxicillin or metroinidazol).
Unfortunately, nowadays the number of cases of infections due to “resistant” stains has been increased sharply due to the development of sophisticated mechanisms to escape the action of antibiotics, known as “antibiotic resistance”. In other words, these antibiotics are now “well known” by the bacteria losing their effectiveness, which varies among different regions of the world, for example, resistance to clarithromycin in the south of Europe is 20%, 15% in Japan and 24% in China. Hence, there is great interest worldwide, both scientific and institutional, for the development of new antibiotics, i.e. “unknown compounds by the bacteria” that can be used in these more difficult cases. It is important not only to develop new compounds, but also to achieve “a new mechanism of action to catch unaware the bacterium” and, as a consequence, it would be more easily removed. With that goal, CiQUS researchers explored a novel strategy and whose first achievements were highlighted on the cover of the American journal last month.
The compounds developed by the González Bello´s group in the CiQUS block the action of the shikimate kinase enzyme, which is used by the bacterium to self-generate the necessary components to grow and spread. The novelty of the discovery is the way that the compounds inhibit the enzyme and it is based on the fact that “the enzymes are not rigid systems” (if so it would be necessary to develop a compound that would fit in the hole, as a “key in a lock”). On the contrary, they are “flexible and dynamic” systems that move – they open and close as the mouth when we eat: the enzyme closes to catalyze the natural transformation in which they are involved, and opens to receive new substance to convert, creating and essential dynamism for the synthesis of compounds that feed the bacteria.
From the detailed knowledge of the enzyme motion “close/active” and “open/inactive” obtained by computational studies, the researchers have developed compounds, which are similar to the one used naturally, that avoid the closure of the enzyme and therefore its natural function. This motion-based strategy, which is new and little explored in the development of inhibitors, allows argeting regions of the active site that a priori would be unnoticed but key in the process and also opens the door to block the action of many other enzymes based on this strategy.
The extensive computational studies, which have been performed through the access of the research group to the supercomputers of the Fundación Pública Galega Centro Tecnolóxico de Supercomputación de Galicia (CESGA), along with the synthesis in the laboratory of numerous candidates have resulted in the identification of two potent inhibitors of the enzyme with an excellent in vitro activity against this bacterium. These excellent results have been possible thanks to the funding by the MINECO within Challenges by the Society program in the Health section. The researchers have recently submitted its renewal to improve, among other things, the already achieved inhibitory potency and also to exploit this methodology in the discovery of novel antibiotics for the treatment of other infectious diseases of high incidence in the hospital environment.