High-throughput screening of sortase inhibitors for antimicrobial therapy
Project is carried out within the European Regional Development Fund (ERDF) activity "Support for science and research"Project identification number: 2010/0233/2DP/184.108.40.206.0/10/APIA/VIAA/032 Project activity period: 36 months (01.01.2011.-31.12.2013.) Project costs: 3456491 LVL
Principle investigator: Dr. biol. Ainārs Leončiks
Nowadays, gram-positive bacteria, such as Staphylococcus aureus, S epidermidis and enterococci often become a cause of the nosocomial or intrahospital diseases. Treatment of these illnesses is complicated because the pathogens inhabiting hospitals are able to evolve immunity to conventional antibiotics. Resistance of staphylococci to β-lactam derivations complicates treatment of many infectious diseases. The strains of methicillin-resistant staphylococci (MRSA) and vancomycin-resistant enterococci have even become a serious problem in healthcare and is also one of the major reasons for the cost increase in medical treatment. New synthetic drugs like vancomycin and other glycopeptide inhibitors of cell wall synthesis that are widely used against MRSA strains do not seem to be a universal medication since cases of partial or total resistance have been described, and therefore the development of new and more efficient antibacterial drugs is still a very important public health issue.
The enzyme sortase A (srtA) associated with cell wall of gram-positive bacteria is considered as one of the most attractive targets for antibacterial therapy. This enzyme plays a major role in the covalent anchoring of the various gram-positive bacteria surface proteins to the cell wall and is important for pathogen survival and reproduction in the host organism. Bacteria with mutations in sortase A gene often are enable to infect host organism or this ability is significantly reduced, so the inhibitors of sortase A activity can be considered as potential antimicrobial agents against pathogen strains resistant to conventional antibiotics.
The most widespread approaches that are used for enzyme inhibitor selection are following: (1) screening of the plant extract chromatography fractions and identification of inhibitors, (2) determination of possible inhibitor structures in silico, (3) screening of the chemical compound libraries, which has a substantial advantage as high throughput.
The aim of this project "High-throughput screening of sortase inhibitors for antimicrobial therapy" is to select the sortase A inhibitors and evaluate their inhibitory activity by using both in vitro and in vivo models. The high throughput screening of the compound library will be used as an approach for selection of potential inhibitory candidates. All potential lead substances that will show selective inhibitory activity will undergo further structural modifications in order to increase inhibiting properties. Simultaneously, we plan to develop innovative technology for organic synthesis of the best drug candidates in order to optimize material and energy consumption and to achieve a high homogeneity of the end-product thus making the research results more available for introduction in pharmaceutical industry.