Studies on the Mode of Action of Quinolone and Pyridone Coccidiostats

Abstract

The primary action of the anticoccidial drugs methyl benzoquate, buquinolate, and meticlorpindol is to prevent the growth of, rather than to kill, coccidia. In the case of Eimeria tenella in the chick, only the sporozoite when it has first invaded the host cell is susceptible to this action, but this is due not to lack of susceptibility of later stages, but rather to failure of the drug to penetrate deep into the gut wall. Later stages of E. brunetti are susceptible to methyl benzoquate given in the food as are later stages of E. tenella if the drug is given intravenously or the experiments are carried out in the chick embryo. Methyl benzoquate given intravenously in the chick forms a depot, mainly in the lung, which is able to protect against lethal coccidial challenges for several weeks. No success has been achieved in explaining the mode of action of the drugs at a molecular level, although the observations would be consistent with an inhibition of nucleic acid synthesis. The earliest compounds found to have marked anticoccidial activity were the sulphonamides, and as with bacteria, it has been shown that these act as competitive inhibitors of p-aminobenzoic acid (Horton-Smith and Boyland, 1946; Waletzky and Hughes, 1946). During studies involving treatment with varying concentrations of sulphadimidine over restricted parts of the life cycle of Eimeria tenella, it was shown (Kendall and McCullough, 1952; Davies and Kendall, 1954a, b) that the stages of the parasite present 72 to 96 hr after infection were most sensitive to the drug, whereas those present during the first 24 hr of the infection were only influenced by very high concentrations of sulphonamide. Moreover, although second generation schizonts appeared to be killed by sulphadimidine, early treatment of infections led only to suppression of the parasite, which was able to continue its development if the drug were later withdrawn. Potentiation of sulphonamides with substances such as pyrimethamine or diaveridine rely on the ability of the potentiator to interfere with the folic acid pathway in the parasite (Joyner and Kenldall, 1956). Amprolium was developed as a coccidiostat during a program of work on thiamine antagonists, and its anticoccidial activity can be annulled by thiamine in the chick (Rogers et al., 1960; Rogers, 1962) or in the chick embryo (Ryley, 1968). The present studies were undertaken in an attempt to throw some light on the mode of action of Received for publication 28 July 1967. the newly introduced quinolone coccidiostats methyl benzoquate (I.C.I. 55,052) (Bowie et al., 1967; Ryley, 1967) and buquinolate (Spencer et al., 1966) and the pyridone, meticlorpindol (Stock et al., 1967).