Quinolone-mediated bacterial death - PubMed (original) (raw)

Review

Quinolone-mediated bacterial death

Karl Drlica et al. Antimicrob Agents Chemother. 2008 Feb.

No abstract available

Figures

FIG. 1.

Schematic representation of quinolone action with gyrase as the primary target. (Step a) Binding of gyrase to DNA. (Step b) Reversible formation of quinolone-gyrase-DNA complexes that rapidly block DNA replication. Step b1 depicts binding of quinolone to gyrase-DNA complexes before DNA cleavage; step b2 represents binding after DNA cleavage. (Step c) Inhibition of replication leads to induction of the SOS response and cell filamentation. (Step d) Lethal chromosome fragmentation that requires ongoing protein synthesis in aerobic conditions, as seen with nalidixic acid treatment of E. coli. (Step e) Lethal chromosome fragmentation that requires on-going protein synthesis but not aerobic conditions, as seen with norfloxacin treatment of E. coli. (Step f) Lethal chromosome fragmentation that requires neither ongoing protein synthesis nor aerobic conditions, as seen for PD161144 with E. coli. (Step g) DNA breakage detected after treatment of cell lysates with an ionic detergent such as SDS. Not shown are effects on transcription. Question marks indicate uncertainty about slow death and the nature of the DNA ends.

FIG. 2.

Sketch of dimerized GyrA59 fragment with DNA and protein gates closed. GyrA-GyrA dimer interfaces are located along the axis of symmetry; arrows point to helix-4 of each GyrA subunit and to positions of E. coli amino acid number 67.

FIG. 3.

Quinolone structures. Positions in the core ring structure are numbered for ciprofloxacin.

FIG. 4.

Fluoroquinolone orientation and cleaved-complex destabilization. (A) Proposed orientation of fluoroquinolone on helix-4 of GyrA dimer. Fluoroquinolones are shown as arrows, with the arrowheads representing the C-7 ring moieties. Each cylinder represents the α-helix-4 of a GyrA subunit (N and C indicate the amino- and carboxy-terminal orientations of helix-4, respectively). The dashed line indicates the axis of symmetry at the GyrA dimer interface. Elements of the figure are not drawn to scale. (B) Proposed chromosome fragmentation arising from cleaved complex destabilization by some fluoroquinolones. Two GyrA subunits, shown as a dimer with GyrB omitted for clarity, are attached covalently to the 5′ end of cleaved DNA. Fluoroquinolone at a moderate concentration (arrow) binds to helix-4 and traps gyrase on DNA. At higher fluoroquinolone concentration, the GyrA subunits separate, thereby fragmenting the chromosome.

References

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Quinolone-mediated bacterial death - PubMed (original) (raw)