Mycobacterial topoisomerase

Mycobacterial topoisomerases are essential enzymes responsible for managing the topological constraints of DNA during replication, transcription, and chromosome segregation (UniProt P9WG47, P9WG53). In Mycobacterium tuberculosis, the repertoire is uniquely limited to DNA topoisomerase I (TopoI) and DNA gyrase, as the organism lacks topoisomerase IV (PubMed: 21572124). DNA gyrase, a heterotetramer composed of GyrA and GyrB subunits, is the primary target of fluoroquinolones like moxifloxacin and levofloxacin, which are cornerstones of second-line multidrug-resistant tuberculosis (MDR-TB) treatment (WHO TB Guidelines). These drugs act by trapping the enzyme in a covalent complex with DNA, preventing ligation and causing lethal double-strand breaks. TopoI is also being explored as a novel target to overcome existing resistance mechanisms (PubMed: 30201675). Given their vital role in bacterial viability and structural divergence from human counterparts, mycobacterial topoisomerases remain high-priority targets for antimicrobial drug discovery. The development of inhibitors targeting the ATPase domain of GyrB or the DNA-binding domain of TopoI represents a promising strategy for next-generation antitubercular therapy.

Other names

DNA gyraseDNA topoisomerase IType II topoisomeraseType IA topoisomeraseGyrA/GyrB complexTopo ITopo IIMycobacterial DNA gyrase

Fluoroquinolones bind to the DNA-gyrase complex, stabilizing the cleavable complex and preventing the re-sealing of DNA strands, which leads to chromosomal fragmentation and cell death (StatPearls: Fluoroquinolones). Other inhibitors, such as aminocoumarins, competitively inhibit the ATPase activity of the GyrB subunit (PubMed: 12644441).