The widespread emergence of bacterial resistance to antibiotics is one of the greatest challenges and means that antibacterial drugs with new mechanisms of action must be developed. Antibiotic resistance is affecting humanity worldwide, increasing morbidity and mortality and thus seriously threatening public health. The antibiotic resistance crisis can be attributed to the adaptation of microorganisms, the overuse and misuse of drugs, and also the lack of development of new drugs.
The biosynthesis of the peptidoglycan of the bacterial cell wall is a complex process involving many steps. All steps represent potential targets for the discovery of new antibacterial agents, as intact peptidoglycan is crucial for bacterial survival and specific to prokaryotic cells. Several agents have been discovered that target the late stages of peptidoglycan biosynthesis, and recent efforts have been made to develop clinically useful Mur enzyme inhibitors. The broad-spectrum antibiotic fosfomycin is still the only clinically useful MurA inhibitor, but experts are working to find new agents that could replace it.
In the Department of Pharmaceutical Chemistry, some hits on the MurA enzyme were obtained after preliminary enzyme assays of commercially available compounds. The HPLC analysis performed showed purity of 90-95% for some compounds, but after purification by chromatographic methods, the compounds were no longer active. This prompted us to investigate the cause of false positive results. We hypothesized that small amounts of impurities structurally similar to the analyzed compounds might be present in the originally tested samples. Therefore, as part of the master's thesis, we synthesized a series of compounds that are structural analogs of the original hits and could be responsible for the action on the MurA enzyme. After biochemical tests, it turned out that even these compounds did not act on the enzyme at the expected concentrations, or only very weakly active. We concluded that it is not the synthesized compounds that are responsible for the initial activity, but other impurities. However, we have identified a compound that could be used for further development, if we manage to improve its activity through chemical transformation of the compound.
|
