Fluoroquinolones are a class of synthetic broad-spectrum antibiotics used to treat bacterial infections. They are effective against various Gram-positive and Gram-negative bacteria. Their design, including a fluorine atom, enhances their ability to inhibit bacterial enzymes and enter bacterial cells.
Essential Bacterial DNA Management
Bacterial survival and reproduction depend on the precise management of their DNA. DNA within a bacterial cell undergoes constant processes such as replication, repair, and compaction. Enzymes known as topoisomerases are essential for modifying the shape and supercoiling of the bacterial chromosome.
Two specific bacterial enzymes, DNA gyrase (topoisomerase II) and topoisomerase IV, are essential for these processes. DNA gyrase introduces negative supercoils into DNA, necessary for initiating DNA replication and relieving positive superhelical twists that accumulate during replication. Topoisomerase IV plays a primary role in the final stages of DNA replication by separating the interlinked daughter chromosomes. Both enzymes function by creating a temporary double-strand break in DNA, passing another DNA strand through the break, and then resealing it.
Targeting DNA Gyrase and Topoisomerase IV
Fluoroquinolones exert their antibacterial effect by inhibiting bacterial DNA gyrase and topoisomerase IV. These drugs bind to both the enzymes and the bacterial DNA, forming a “ternary complex.” This complex traps the enzymes on the DNA, preventing them from performing their normal functions of breaking and rejoining DNA strands.
By stabilizing this complex, fluoroquinolones block DNA strand passage and disrupt the DNA replication machinery. This leads to the accumulation of persistent DNA breaks and causes replication forks to stall. Different fluoroquinolones may have varying primary targets depending on the bacterial species; DNA gyrase is often the more sensitive target in Gram-negative bacteria, while topoisomerase IV is typically more sensitive in Gram-positive bacteria. The binding occurs at the interface between the protein and DNA, near the active site, and appears to induce changes in both the DNA and the topoisomerase.
The Lethal Effect on Bacterial Cells
The inhibition of DNA gyrase and topoisomerase IV by fluoroquinolones has severe consequences for bacterial cells. The accumulation of unrepaired DNA breaks and the inability to properly replicate DNA generate extensive cellular damage. This disruption blocks DNA synthesis and triggers a cascade of events within the bacterial cell.
The overwhelming damage leads to bacterial cell death, often through apoptosis-like mechanisms. This direct cellular injury distinguishes fluoroquinolones as bactericidal agents, meaning they actively kill bacteria, rather than merely inhibiting their growth (bacteriostatic). The damage can also involve chromosome fragmentation and the generation of reactive oxygen species.
Understanding Bacterial Resistance
Bacteria can develop resistance to fluoroquinolones, which often relates to the drug’s mechanism of action. The most common way bacteria become resistant involves mutations in the genes that encode DNA gyrase (GyrA and GyrB subunits) and topoisomerase IV (ParC and ParE subunits). These mutations, particularly in the quinolone resistance-determining region (QRDR), alter the structure of the enzymes. This structural change reduces the drug’s ability to bind effectively, diminishing its antibacterial effect.
Another mechanism of resistance involves efflux pumps, which are bacterial proteins that actively pump the antibiotic out of the cell before it can reach its target. These pumps can expel various antimicrobial agents, including fluoroquinolones. Understanding these resistance mechanisms is important for maintaining the effectiveness of fluoroquinolone antibiotics.