点击显示 收起
Departments of Epidemiology and Microbiology, University of North Carolina, Chapel Hill
Department of Biochemistry, Dartmouth Medical School, Hanover, New Hampshire
Wichmann et al. [1] recently demonstrated, in a cross-sectional study of 504 cases of malaria imported to western and central Europe, that single-nucleotide polymorphisms in the cytochrome b codon 268 were not common and did not predict atovaquone resistance in Plasmodium falciparum. Although that study clearly demonstrated that codon 268, by itself, does not account for all atovaquone resistance, we would like to caution readers to not interpret the results to suggest that cytochrome b mutations are not useful molecular markers.
The poor correlation between the codon 268 mutation and atovaquone resistance is not surprising; in a 1996 review [2], mutations in almost 40 different cytochrome b loci were associated with resistance to inhibitors. Numerous different mutations have also been found in Pneumocystis jirovecii cytochrome b, probably because atovaquone is also used clinically as prophylaxis against P. jirovecii pneumonia (PCP). In 2 published studies of patients with PCP who had been exposed to atovaquone, 7 different nonsynonymous mutations in the Qo site were found, only 2 of which were seen in >1 patient [3, 4]. Cytochrome b is encoded in the mitochondrial genome, where replication has a 10-fold higher error rate [5]. The resulting high rate of mutation might explain not only the multiplicity of mutations but also why atovaquone resistance occurs readily when it is administered as a single agent [6].
Thus, specific point mutations in cytochrome b are unlikely to be useful in surveillance for atovaquone resistance. Methods that can pick up multiple mutationssuch as high-throughput sequencing, single-strand conformation polymorphisms, and heteroduplex tracking assaysmay be more appropriate.
References
1. Wichmann O, Muehlberger N, Jelinek T, et al. Screening for mutations related to atovaquone/proguanil resistance in treatment failures and other imported isolates of Plasmodium falciparum in Europe. J Infect Dis 2004; 190:15416. First citation in article
2. Brasseur G, Saribas AS, Daldal F. A compilation of mutations located in the cytochrome b subunit of the bacterial and mitochondrial bc1 complex. Biochim Biophys Acta 1996; 1275:619. First citation in article
3. Kazanjian P, Armstrong W, Hossler PA, et al. Pneumocystis carinii cytochrome b mutations are associated with atovaquone exposure in patients with AIDS. J Infect Dis 2001; 183:81922 (erratum: J Infect Dis 2001; 183:1170). First citation in article
4. Walker DJ, Wakefield AE, Dohn MN, et al. Sequence polymorphisms in the Pneumocystis carinii cytochrome b gene and their association with atovaquone prophylaxis failure. J Infect Dis 1998; 178:176775. First citation in article
5. Alberts B, Bray D, Lewis J, Raff M, Roberts K, Watson JD. Molecular biology of the cell. 2nd ed. New York: Garland, 1989. First citation in article
6. Looareesuwan S, Viravan C, Webster HK, Kyle DE, Hutchinson DB, Canfield CJ. Clinical studies of atovaquone, alone or in combination with other antimalarial drugs, for treatment of acute uncomplicated malaria in Thailand. Am J Trop Med Hyg 1996; 54:626. First citation in article