Malarone treatment failure and in vitro confirmation of resistance of Plasmodium falciparum isolate from Lagos, Nigeria

Abstract

We report the first in vitro and genetic confirmation of Malarone (GlaxoSmithKline; atovaquone and proguanil hydrochloride) resistance in Plasmodium falciparum acquired in Africa. On presenting with malaria two weeks after returning from a 4-week visit to Lagos, Nigeria without prophylaxis, a male patient was given a standard 3-day treatment course of Malarone. Twenty-eight days later the parasitaemia recrudesced. Parasites were cultured from the blood and the isolate (NGATV01) was shown to be resistant to atovaquone and the antifolate pyrimethamine. The cytochrome b gene of isolate NGATV01 showed a single mutation, Tyr268Asn which has not been seen previously.

Figure 1

Sequence analysis of P. falciparum CYT b gene from isolate NGATV01 showing codons 70 to 309. Residue 268 highlighted shows the change from tyrosine (Y) to asparagine (N) compared to atovaquone-sensitive strain K1 and the change to serine (S) in the atovaquone-resistant strain TM93-C1088 [6].

Figure 2

Atovaquone (ATV) in P. falciparum cytochrome b active site. A: Atovaquone built and docked using HyperChem release 6, in the active site of a model of P. falciparum cytochrome B. Homology model prepared using the structure of the chicken enzyme [14] with the aid of the SWISS-MODEL Protein Modelling Server and observed in the Swiss Model Viewer [15]. B: As A, with active site tyrosine268 replaced by asparagine.