Photocleavage of DNA by the fluoroquinolone antibacterials.

We have determined the relative efficiencies for the formation of single strand breaks (ssbs) after the UVA irradiation of pBR322 DNA and various fluoroquinolone (fleroxacin, lomefloxacin, norfloxacin) and naphthyridine (nalidixic acid, enoxacin) antibacterials. After correcting for the differences in absorption, the relative order for DNA photocleaving activity under anaerobic conditions is: fleroxacin, lomefloxacin > nalidixic acid >> norfloxacin > enoxacin. In general, fluoroquinolones having fluorine substituents at the C-6 and C-8 positions (lomefloxacin and fleroxacin) are 10-fold more efficient in generating ssbs than those having only a C-6 fluorine atom (norfloxacin). The effect of oxygen on photoinduced DNA damage caused by these antibacterials is complex, but our data imply that active oxygen species are not necessary for DNA scission by these molecules, and indeed, may sometimes inhibit it. Lomefloxacin ethyl ester, which cannot undergo decarboxylation, is as active as lomefloxacin itself. Thus the free radical generated by decarboxylation is unlikely to be the active species involved in photoinduced fluoroquinolone DNA cleavage. For lomefloxacin and fleroxacin, DNA damage probably results from the generation of a carbene at C-8 as a result of photoinduced loss of their F8 atom as fluoride upon UVA irradiation. Fluoroquinolones lacking a C-8 fluorine atom must operate by a different mechanism. While photocleavage of pBR322 DNA does not necessarily mean that duplex DNA will be cleaved under the same conditions, nevertheless lomefloxacin and fleroxacin, the two most photogenotoxic fluoroquinolones, did cause the most damage to the plasmid DNA.