[Mechanism of action of quinolones]

Abstract

How do the quinolones inhibit bacteria? The chromosome of bacteria is composed of helical double-stranded DNA and contains 60 to 70 spatial regions of organisation, termed domains of supercoiling. Each domain is about 20 mu long, attached to an RNA core and is organised by supercoiling which occurs quite independently of the DNA coiling in any other domain. Supercoiling is controlled by the enzyme DNA gyrase, which introduces transient breaks into both DNA strands of each domain, removes about 400 turns from its DNA helix, then reseals the DNA so locking in the supercoiling. This supercoiled state is essential to the well-being of bacteria as it enables them to accommodate their chromosome (1300 mu long) within the confines of their cell envelope (2 mu X 1 mu). The target site of action of the quinolone antibacterial agents is DNA gyrase and its inhibition by them sets off a complex series of events which ultimately causes bacteria to die. However, the bactericidal action of nalidixic acid and most other quinolones can be abolished if protein synthesis is inhibited by chloramphenicol, and perhaps not surprisingly the same is true if RNA synthesis is inhibited by rifampicin. With ofloxacin and ciprofloxacin the situation is more complicated because protein or RNA synthesis inhibition does not completely abolish their bactericidal effects. Hence ofloxacin and ciprofloxacin exhibit a qualitative difference from most other quinolone antibacterial agents in that they possess an additional mechanism of killing bacteria that is not possessed by the older, lesser active drugs. How can these quinolones kill bacteria without harming man? Mammalian cells possess an enzyme which resembles bacterial DNA gyrase in that it cuts double-stranded DNA in a similar manner. However, the mammalian enzyme does not possess any supercoiling action nor is it susceptible to inhibition by the quinolone antibacterials, which can hence be used to inhibit bacteria in man without harm to the latter.