Goraksha Khose and Elvar Viktorsson
Introduction:
There is an urgent need for new antitubercular agents. Fast evolvement of antimicrobial resistance (AMR) in the form of Multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of M. tuberculosis (Mtb) are major global concerns. In 2023, WHO outlined 40 research priorities on AMR, seven of which focused on drug-resistant Mtb. Also, the 2023 WHO Global TB report gave estimates of 10.6 million new cases and 1.6 million deaths in 2022, with over 450 thousand new rifamycin-resistant TB cases. Myxin, a phenazine class compound, shows promising nanomolar potency against Mtb (H37Rv).
Method:
Four different phenazine scaffolds derived from the natural product myxin were synthesized. The scaffolds were subjected to conventional structure-activity relationship studies (SAR) to enhance potency, reduce toxicity to mammalian cell lines, and improve aqueous solubility. Based on the biological results, the most promising derivatives were furthermore selected for additional studies in resistant clinical isolates. Our synthesis focuses on providing biodegradable prodrug analogs of each scaffold with enhanced aqueous solubility.
Results:
At this point in the project, 4 phenazine scaffolds and more than 50 different derivatives have been synthesized. A REMA assay was employed to assess their activity against a virulent strain of M. tuberculosis (H37Rv), while cytotoxicity was evaluated against NRK and H9c2 cells.
Conclusion:
The results confirm that at least 4 compounds (IMICE_04, IMICE_22, IMICE_28, and IMICE_32) have highly potent antimycobacterial activities. The selected compound was assessed for cytotoxicity and found to be non-toxic against human healthy kidney cell lines and lung cell lines.
