Isonicotinic acid hydrazide: an anti-tuberculosis drug inhibits malarial transmission in the mosquito gut

Abstract

We studied the transmission-blocking effect of isonicotinic acid hydrazide (INH), a widely used anti-tuberculosis drug, against Plasmodium gallinaceum and Plasmodium berghei. INH-treatment of infected animals did not inhibit parasite development in the blood of the vertebrate host, but did inhibit exflagellation, ookinete formation, and oocyst development in the mosquito. Oocyst development was inhibited in a dose-dependent manner. The ED 50 in the P. gallinaceum/chicken/ Aedes aegypti model and P. berghei/mouse/ Anopheles stephensi model was 72 and 109 mg/kg, respectively. In marked contrast, in vitro exflagellation and ookinete development were not directly affected by physiological concentrations of INH. We suggest that INH exerts its inhibitory effects on the mosquito stages of the malaria parasite by an indirect, and at present undefined mechanism. Further elucidation of the mechanism how INH inhibits parasite development specifically on mosquito stages may allow us to identify new targets for malaria control strategy. Index Descriptors and Abbreviations: Plasmodium berghei; Plasmodium gallinaceum; Anopheles stephensi; Aedes aegypti; Transmission-blocking anti-malarial; INH, isonicotinic acid hydrazide; XA, xanthurenic acid; GAF, gametocyte activating factor; HBSA, Hepes-buffered suspended animation medium; EI, exflagellation index; ED 50, half-maximal effective dose