Bacillus anthracis topoisomerase IV (Topo IV)

Bacillus anthracis topoisomerase IV is an essential type II topoisomerase enzyme responsible for the decatenation and segregation of daughter chromosomes during bacterial DNA replication (Aldred et al., 2014; UniProt). It exists as a heterotetramer composed of two GrlA (ParC) and two GrlB (ParE) subunits, which work together to manage DNA topology by introducing transient double-strand breaks (Aldred et al., 2012). This enzyme is a critical therapeutic target for fluoroquinolone antibiotics, such as ciprofloxacin, which are frontline treatments for anthrax (NIH; PubMed). Quinolones act by stabilizing the enzyme-DNA cleavage complex, effectively converting the enzyme into a cellular toxin that generates lethal DNA damage (Hooper, 1997). However, the emergence of resistance through specific mutations in the GrlA and GrlB subunits, such as Ser81 mutations, poses a significant challenge, particularly given the status of B. anthracis as a potential bioweapon (Aldred et al., 2012). Recent drug development efforts have focused on novel bacterial topoisomerase inhibitors (NBTIs) that target distinct sites to overcome existing resistance mechanisms (Mitton-Fry et al., 2025).

Other names

DNA topoisomerase IVGrlA/GrlB complexParC/ParE complexType II topoisomerase

Fluoroquinolones stabilize the covalent enzyme-DNA cleavage complex, preventing the religation of DNA strands and leading to lethal double-strand breaks (Aldred et al., 2012). Novel bacterial topoisomerase inhibitors (NBTIs) like gepotidacin bind to a distinct site between the two subunits and induce single-stranded DNA breaks, allowing them to bypass common quinolone resistance mutations (Mitton-Fry et al., 2025).