Novel anti-bacterial drugs
In the drug design arena, the technological tools and methods are constantly evolving. Structural biology and combinatorial chemistry have been superseded by high-throughput screening of chemical libraries. Technologies such as molecular cell biology, in silico modelling, genetic engineering and NMR are also heavily used in drug design. As a result, concerted efforts are necessary to attain the multidisciplinary expertise required for drug design. To address this, the EU-funded STARS (Scientific Training in Antimicrobial Research Strategies) project brought together 12 partners from universities, research centres and the private sector under the same umbrella. The key objective was to design new drugs against bacterial two-component systems (TCSs). These serve as a basic stimulus-response coupling mechanism that enables organisms to receive and respond to environmental cues. The consortium performed a series of in silico, in vitro and in vivo experiments to search for new compounds and design novel inhibitors. Alongside drug design methodologies, they developed cheminformatics databases to support the search for new compounds. A series of computational screening experiments led to the identification of compounds for further experimental validation. Among these, researchers discovered novel inhibitors against histidine kinase enzymes inhibiting the growth of various Staphylococcus and Streptococcus strains. Biochemical and computational studies unveiled that these molecules work by competing with the binding of ATP to the kinase enzyme, and scientists envisage their use could extend to antibiotic resistant strains. With respect to the tuberculosis causative agent Mycobacterium tuberculosis (Mtb), the consortium concentrated on one TCS responsible for Mtb going into latency. They studied this TCS at the structural and functional level, and obtained important insight into the amino acid sequence responsible for TCS activation. Considering the millions of tuberculosis-associated deaths caused every year, targeting highly drug-resistant Mtb strains is highly desirable. The STARS platform of drug design extends beyond bacterial infections to the malaria-causing parasite Plasmodium falciparum. Studying pathogen invasiveness and identifying targets of inhibitor binding unveils novel structural requirements of inhibitors. This information is fundamental for the development of novel drugs.
Keywords
Antibiotic resistance, drug design, inhibitor, Staphylococcus, Streptococcus, tuberculosis, malaria
