Menoctone resistance in malaria parasites is conferred by M133I mutations in cytochrome b that are transmissible through mosquitos [PublishAheadOfPrint]

Malaria related mortality has slowly decreased over the past decade; however, eradication of malaria requires the development of new antimalarial chemotherapies that target liver stages and combat the emergence of drug resistance. The diminishing arsenal of anti-liver stage compounds sparked our interest in reviving the old and previously abandoned compound menoctone. In support of these studies we developed a new convergent synthesis method that was facile, required fewer steps, produced better yields, and utilized less expensive reagents than the previously published method. Menoctone proved to be highly potent against liver stages of Plasmodium berghei (IC₅₀ = 0.41 nM) and erythrocytic stages of P. falciparum (113 nM). We selected for resistance to menoctone and found M133I mutations in cytochrome b of both P. falciparum and P. berghei. This same mutation has ben observed previously in atovaquone resistance and we confirmed cross-resistance between menoctone and atovaquone in vitro (P. falciparum) and in vivo (P. berghei). Finally we assessed the transmission potential of menoctone-resistant P. berghei and found the M133I mutant parasites were readily transmitted from mouse to mosquitos and back to mice. In each step M133I mutation in cytochrome b of menoctone resistance was confirmed. In summary this study is the first to show the mechanism of resistance to menoctone and that menoctone and atovaquone resistance is transmissible through mosquitos.

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