Recently, due to the widespread emergence of resistance, the need for new antibiotics has grown sharply, as some infections can no longer be treated with available drugs. A promising class of new agents are the novel bacterial topoisomerase inhibitors (NBTIs). These bind to the bacterial enzymes DNA gyrase and topoisomerase IV and disable the normal process of DNA replication and transcription, leading to cell death. Structurally, they consist of three parts, the bicyclic left part, which binds to DNA, a linker, and the aromatic right part, which binds to the hydrophobic binding site of enzyme. According to previous studies, the main challenge of these agents is to achieve an appropriate balance between antibacterial activity and cardiotoxicity associated with unwanted binding to hERG channels.
In this master's thesis, we designed and synthesized twelve compounds from the NBTI class. In six of them, we wanted to improve the stability and maintain the activity by bioisosteric replacement of the amide with a triazole ring. In two, we introduced a more polar linker and studied the effect on activity. In the others, fluorine was attached to position 3 of the naphthyridine skeleton to extend its activity to gram-negative bacteria. We used various linkers that had been previously evaluated. All compounds were analysed by 1H NMR, 13C NMR, HRMS, ATR-FTIR and HPLC methods.
The antibacterial activity was evaluated on many bacterial strains. The results showed that triazole compounds have good activity against Gram-positive strains such as Staphylococcus aureus and MRSA. Compounds with a more polar linker did not show positive results, on the other hand, compounds with fluorine at position 3 of naphthyridine inhibited the growth of not only Gram-positive, but also Gram-negative strains. By introducing fluorine onto the naphthyridine skeleton, we have significantly improved the activity. Three compounds with the lowest minimal inhibitory concentration values (34, 25 and 27) were additionally tested for their ability to inhibit the formation of S. aureus biofilm and cause the disintegration of already formed biofilm. We also performed acute toxicity testing on zebrafish embryos and treatment efficacy of embryos, deliberately infected with S. aureus. We found that all three compounds have good safety profiles and they successfully rescued embryos from lethal infection. Considering the promising results, further in vivo studies of these compounds are required. They may also serve as lead compounds for further modifications.
|
