What is the mechanism of action of gepotidacin (Gepotidacin), a novel bacterial topoisomerase inhibitor?

From the Guidelines

Gepotidacin works by inhibiting bacterial DNA replication through a unique dual-targeting mechanism, selectively binding to DNA gyrase and topoisomerase IV, which prevents the enzymes from functioning properly and ultimately leads to bacterial cell death. This mechanism of action is particularly valuable because it remains effective against bacteria that have developed resistance to fluoroquinolones, which target the same enzymes but at different binding sites 1. The unique binding profile of gepotidacin makes it less susceptible to existing resistance mechanisms, providing a potential treatment option for infections caused by multidrug-resistant pathogens.

Key Points

• Gepotidacin is a triazaacenaphthylene antibiotic that inhibits bacterial DNA replication
• It selectively binds to two bacterial enzymes: DNA gyrase and topoisomerase IV, at sites distinct from where fluoroquinolones bind
• This dual inhibition prevents the enzymes from functioning properly, which blocks DNA replication and ultimately leads to bacterial cell death
• Gepotidacin's mechanism is particularly valuable because it remains effective against bacteria that have developed resistance to fluoroquinolones
• The unique binding profile of gepotidacin makes it less susceptible to existing resistance mechanisms, providing a potential treatment option for infections caused by multidrug-resistant pathogens, as noted in a recent study published in The Lancet Infectious Diseases 1.

From the FDA Drug Label

BLUJEPA is a triazaacenaphthylene antibacterial that inhibits Type II topoisomerases including bacterial topoisomerase II (DNA gyrase) and topoisomerase IV, thereby inhibiting DNA replication. The mechanism of action of gepotidacin is through the inhibition of Type II topoisomerases, which includes bacterial topoisomerase II (DNA gyrase) and topoisomerase IV. This inhibition leads to the disruption of DNA replication, resulting in bactericidal activity against pathogens. 2

From the Research

Mechanism of Action of Gepotidacin

• Gepotidacin is a first-in-class triazaacenaphthylene novel bacterial topoisomerase inhibitor (NBTI) that inhibits bacterial DNA replication 3, 4, 5, 6.
• The compound has been shown to be a potent inhibitor of gyrase-catalyzed DNA supercoiling and relaxation of positively supercoiled substrates 3.
• Gepotidacin induces high levels of gyrase-mediated single-stranded breaks, but not double-stranded breaks, even at high concentrations or in the presence of ATP 3, 4.
• The mechanism of action of gepotidacin is distinct from that of fluoroquinolones, which induce primarily double-stranded DNA breaks 3.
• Gepotidacin forms gyrase-DNA cleavage complexes that are stable for >4 h and competes with fluoroquinolones for binding to gyrase 3.

Interaction with Bacterial Targets

• Gepotidacin has been shown to interact with both gyrase and topoisomerase IV in Escherichia coli, with well-balanced dual-targeting of these enzymes 4.
• Mutations in GyrA and ParC amino acid residues that interact with gepotidacin alter the activity of the compound against the enzymes and reduce the antibacterial activity of gepotidacin against mutant strains 4.
• Gepotidacin has been shown to be effective against a range of wild-type and fluoroquinolone-resistant bacteria, including Staphylococcus aureus, Streptococcus pneumoniae, and Escherichia coli 3, 5, 6.

In Vitro Activity

• Gepotidacin has been shown to have in vitro activity against a broad spectrum of bacterial pathogens, including Gram-positive and Gram-negative bacteria 5, 6.
• The MIC90 of gepotidacin for various bacterial isolates has been reported to be in the range of 0.25-4 μg/ml 5, 6.
• Gepotidacin has been shown to be bactericidal against S. aureus, S. pneumoniae, and E. coli, with MBC/MIC ratios of ≤4 against 98, and 88% of the isolates tested, respectively 5.