Kahakamide A isolated from Nocardiopsis dassonvillei Tb8 novel strain is a DNA gyrase inhibitor

The search for new biologically active substances as well as the study of the mechanisms of action of previously described antimicrobial metabolites, still remain priority areas of fundamental chemical and biological research, since the results of such work can help in overcoming the growing antibiotic resistance of pathogenic microorganisms. Modern approaches to search for bioactive compounds using high-throughput screening methods make it possible to discover and study new compounds with high speed and accuracy. An example of such a system is a genetically modified Escherichia coli strain containing the plasmid vector pDualrep2. This genetic construction allows the detection of the antibacterial activity of compounds and the mechanism of action of a specific metabolite. During the search for strains producing promising substances for antimicrobial therapy using the pDualrep2 reporter system, Nocardiopsis dassonvillei strain Tb8, isolated from soil in a tobacco field (Razdolnaya village, Krasnodar Krai) was identified. The produced metabolite of strain Tb8 causes growth suppression of E. coli with tolC gene deletion and induction of SOS-response in bacterial cells. The isolated and purified active substance was identified by HPLC-ESI-qTof as Kahakamide A. The mechanism of action of Kahakamide A through inhibition of DNA synthesis has not been previously described, and for the first time we found the activity of this substance against Klebsiella pneumoniae ATCC 700603, K. pneumoniae ATCC 62867, E. coli ATCC 35705 strains with clinically significant resistance to beta-lactams. The above makes this substance and the target of its action promising for the development of therapeutic drugs. A detailed study of Kahakamide A biosynthesis will be the subject of further research.