Example of antibacterial 4-quinoiones: ciprofloxacin o o A (11.12)

Other examples of antibacterial 4-quinotones: norfloxacin (11,116) oxuiiiiiccid ofloxacin acrosoxacin flumequiiie enoxacin lometlox;iciin (It J17) Sparfloxacin (11.118) temafluxncin (11.119)

Example of 8'Az<*'4-Quinol<me: nalidixic acid o

Example of 8'Az<*'4-Quinol<me: nalidixic acid o



effect on Gram-positive bacteria, but many other members are inhibitory including newer trifluorinated derivatives such as sparfloxacin: see also Section 11.6.6.

The 4-quinolone derivatives inhibit the supercoiling of bacterial DNA by acting on DNA gyrase (topoisomerase II), an enzyme that nicks double-stranded DNA, introduces negative supercoils and then seals the nicked DNA. DNA gyrase is composed of four subunits, two A monomers and two B monomers. Human cells possess a topoisomerase II which, like bacterial DNA gyrase, is able to cut and seal double-stranded DNA. However, this mammalian enzyme is made up of two subunits and does not possess any supercoiling activity; its action must, therefore, be substantially different from that of bacterial DNA gyrase, which is a satisfactory explanation for the selective action of the 4-quinolone derivatives.

One other point about their mechanism of action deserves comment. It has been found that concentrations well in excess of inhibitory levels reduce the bactericidal activity of nalidixic acid and some other members, e.g. norfloxacin, cinoxacin (11.14) and pipemidic (11.15) and piromidic (11.16) acids. Paradoxically, this is believed to arise as a consequence of an inhibition of RNA/protein synthesis at these high drug concentrations. Support for this contention has been obtained by using these drugs in the presence of a known inhibitor, rifampicin (11.17), of RNA synthesis, when their bactericidal effect is abolished. However, ofloxacin and ciprofloxacin are, to some extent, resistant to

Example of 6,&-Di(izo-t-Quinoloiie; FipL'midifj and Piromidic acids

Example of2-Aza-4-Quinoione: cinoxacin

Example of 6,&-Di(izo-t-Quinoloiie; FipL'midifj and Piromidic acids




(I1.17J rifempiciit

rifampicin antagonism in E. coli, since their bactericidal effects were only partially abolished. These findings have yet to be explained fully.

The 4-quinolones are unaffected by plasmid-mediated resistance mechanisms and thus the frequency of clinical resistance, though increasing, is still low.

Rifampicin (11.17), a useful antitubercular antibiotic and a member of the rifamycin group, does not interact with DNA but binds to and inhibits DNA-dependent RNA polymerase with a consequent specific action on RNA synthesis. RNA polymerase from rifampicin-resistant bacteria is not inhibited by the drug. Rifampicin does not bind to or inhibit mammalian DNA polymerase, and hence has a selective toxic action.

11.3.5 Antibacterial folate inhibitors

Sulphonamides (11.18) act by competitively inhibiting dihydropteroate synthetase, an enzyme involved in the production from p-aminobenzoate (PAB (11.19)) of dihydropteroate (11.20) during dihydrofolate (11.21) biosynthesis. This inhibitory effect is reversed by excess PAB. It has also been found that these drugs can replace PAB as a substrate, so that they become incorporated in a false dihydropteroate or dihydrofolate.

(11.18) general structure til' Kulphonamides


(11.19) p-ammobcnzoic acid

(11.20) dihydrtipEeroate h^Ji, NipLcH, N CONH-ÇH-COOH


(11.21) dihydrofolate



(11.22) trimethoprim

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