Development of narrow-spectrum topoisomerase-targeting antibacterials against mycobacteria

Sterle, Masa and Habjan, Eva and Piga, Martina and Persolja, Peter and Durcik, Martina and Dernovsek, Jaka and Szili, Petra and Czikkely, Márton Simon and Zidar, Nace and Janez, Ilas and Pál, Csaba and Accetto, Tomaz and Pardo, Luis A. and Kikelj, Danijel and Masic, Lucija Peterlin and Tomasic, Tihomir and Bitter, Wilbert and Cotman, Andrej Emanuel and Speer, Alexander and Zega, Anamarija (2024) Development of narrow-spectrum topoisomerase-targeting antibacterials against mycobacteria. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 276. ISSN 0223-5234

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Abstract

New 2-pyrrolamidobenzothiazole-based inhibitors of mycobacterial DNA gyrase were discovered. Among these, compounds 49 and 51, show excellent antibacterial activity against Mycobacterium tuberculosis and Mycobacterium abscessus with a notable preference for mycobacteria. Both compounds can penetrate infected macrophages and reduce intracellular M. tuberculosis load. Compound 51 is a potent inhibitor of DNA gyrase (M. tuberculosis DNA gyrase IC50 = 4.1 nM, Escherichia coli DNA gyrase IC50 of <10 nM), selective for bacterial topoisomerases. It displays low MIC90 values (M. tuberculosis: 0.63 <mu>M; M. abscessus: 2.5 mu M), showing specificity for mycobacteria, and no apparent toxicity. Compound 49 not only displays potent antimycobacterial activity (MIC90 values of 2.5 mu M for M. tuberculosis and 0.63 mu M for M. abscessus) and selectivity for mycobacteria but also exhibits favorable solubility (kinetic solubility = 55 mu M) and plasma protein binding (with a fraction unbound of 2.9 % for human and 4.7 % for mouse). These findings underscore the potential of fine-tuning molecular properties to develop DNA gyrase B inhibitors that specifically target the mycobacterial chemical space, mitigating the risk of resistance development in non-target pathogens and minimizing harm to the microbiome.

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