DNA Gyrase and Topoisomerase IV (Fluoroquinolone Target)
therapeutic vulnerability
Bacterial DNA gyrase and topoisomerase IV break, pass, and reseal duplex DNA to manage supercoiling and decatenate replicated chromosomes. Fluoroquinolones bind the enzyme-DNA complex via a water-metal-ion bridge, block strand-passage catalysis, and stabilize the cleavage complex; release of the broken DNA underlies their bactericidal activity. Quinolones are the only current class that directly inhibits bacterial DNA synthesis, and their bacterial type II topoisomerase targets are distinct from human topoisomerases, giving selectivity.
Used by disorders
Tularemia
as Francisella DNA Gyrase and Topoisomerase IV
Downstream
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Fluoroquinolone Target Resistance
QRDR mutations and efflux protect the topoisomerase target, escaping fluoroquinolone action.
Show evidence (2 references)
"Quinolones dually target DNA gyrase and topoisomerase IV binding to specific domains and conformations so as to block DNA strand passage catalysis and stabilize DNA-enzyme complexes that block the DNA replication apparatus and generate double breaks in DNA that underlie their bactericidal activity."
Review establishing DNA gyrase and topoisomerase IV as the dual fluoroquinolone target and the cleavage-complex mechanism this node represents. Evidence source is OTHER as this is a review article.
"Quinolone antimicrobials are widely used in clinical medicine and are the only current class of agents that directly inhibit bacterial DNA synthesis."
Establishes fluoroquinolones as the agents that directly inhibit bacterial DNA synthesis at this target. Evidence source is OTHER as this is a review.
Fluoroquinolone Target Resistance
adaptive escape
Resistance to fluoroquinolones arises predominantly from mutations in the quinolone-resistance-determining region (QRDR) of the GyrA and ParC subunits that lower drug-target affinity, from increased efflux-pump expression, and from acquired plasmid-mediated quinolone-resistance genes. High-level resistance is common in some pathogens (e.g. typhoidal Salmonella), which is why fluoroquinolones must be susceptibility-guided rather than assumed effective.
Show evidence (1 reference)
"Mechanisms of resistance include mutational alterations in drug target affinity and efflux pump expression and acquisition of resistance-conferring genes."
Enumerates the fluoroquinolone resistance mechanisms encoded here (target mutation, efflux, acquired genes). Evidence source is OTHER as this is a review article.