Atovaquone is an antiparasitic drug that selectively inhibits electron transport through the parasite mitochondrial cytochrome bc1 complex and collapses the mitochondrial membrane potential at concentrations far lower than those at which the mammalian system is affected. Because this molecule represents a new class of antimicrobial agents, we seek a deeper understanding of its mode of action. To that end, we employed site-directed mutagenesis of a bacterial cytochrome b, combined with biophysical and biochemical measurements. A large scale domain movement involving the iron-sulfur protein subunit is required for electron transfer from cytochrome b-bound ubihydroquinone to cytochrome c1 of the cytochrome bc1 complex. Here, we show that atovaquone blocks this domain movement by locking the iron-sulfur subunit in its cytochrome b-binding conformation. Based on our malaria atovaquone resistance data, a series of cytochrome b mutants was produced that were predicted to have either enhanced or reduced sensitivity to atovaquone. Mutations altering the bacterial cytochrome b at its ef loop to more closely resemble Plasmodium cytochrome b increased the sensitivity of the cytochrome bc1 complex to atovaquone. A mutation within the ef loop that is associated with resistant malaria parasites rendered the complex resistant to atovaquone, thereby providing direct proof that the mutation causes atovaquone resistance. This mutation resulted in a 10-fold reduction in the in vitro activity of the cytochrome bc1 complex, suggesting that it may exert a cost on efficiency of the cytochrome bc1 complex. Atovaquone is an antiparasitic drug that selectively inhibits electron transport through the parasite mitochondrial cytochrome bc1 complex and collapses the mitochondrial membrane potential at concentrations far lower than those at which the mammalian system is affected. Because this molecule represents a new class of antimicrobial agents, we seek a deeper understanding of its mode of action. To that end, we employed site-directed mutagenesis of a bacterial cytochrome b, combined with biophysical and biochemical measurements. A large scale domain movement involving the iron-sulfur protein subunit is required for electron transfer from cytochrome b-bound ubihydroquinone to cytochrome c1 of the cytochrome bc1 complex. Here, we show that atovaquone blocks this domain movement by locking the iron-sulfur subunit in its cytochrome b-binding conformation. Based on our malaria atovaquone resistance data, a series of cytochrome b mutants was produced that were predicted to have either enhanced or reduced sensitivity to atovaquone. Mutations altering the bacterial cytochrome b at its ef loop to more closely resemble Plasmodium cytochrome b increased the sensitivity of the cytochrome bc1 complex to atovaquone. A mutation within the ef loop that is associated with resistant malaria parasites rendered the complex resistant to atovaquone, thereby providing direct proof that the mutation causes atovaquone resistance. This mutation resulted in a 10-fold reduction in the in vitro activity of the cytochrome bc1 complex, suggesting that it may exert a cost on efficiency of the cytochrome bc1 complex. Malaria is one of the most intractable human afflictions in the world. Despite intensive campaigns against the parasitic disease, an estimated 300 to 500 million cases still occur each year. Plasmodium falciparum, the causative agent of the most lethal form of malaria, is responsible for over 2 million deaths annually, largely among young children and pregnant women (1Sachs J. Malaney P. Nature. 2002; 415: 680-685Crossref PubMed Scopus (1419) Google Scholar, 2Snow R.W. Guerra C.A. Noor A.M. Myint H.Y. Hay S.I. Nature. 2005; 434: 214-217Crossref PubMed Scopus (2155) Google Scholar). Efforts to eradicate malaria have not been successful, and the situation may be worsening due, in large part, to the emergence and spread of drug-resistant parasites. The need for new antimalarial drugs is now widely recognized. Atovaquone represents a new class of drugs having a metabolic target different from extant antimalarial drugs to which resistance is widespread. Atovaquone was found to be a very effective antimalarial compound, but unsuitable for use as a single agent because of the relatively quick emergence of resistance (3Chiodini P.L. Conlon C.P. Hutchinson D.B. Farquhar J.A. Hall A.P. Peto T.E. Birley H. Warrell D.A. J. Antimicrob. Chemother. 1995; 36: 1073-1078Crossref PubMed Scopus (73) Google Scholar, 4Looareesuwan S. Viravan C. Webster H.K. Kyle D.E. Hutchinson D.B. Canfield C.J. Am. J. Trop. Med. Hyg. 1996; 54: 62-66Crossref PubMed Scopus (341) Google Scholar, 5Looareesuwan S. Chulay J.D. Canfield C.J. Hutchinson D.B. Am. J. Trop. Med. Hyg. 1999; 60: 533-541Crossref PubMed Scopus (173) Google Scholar). However, in combination with the synergistic agent proguanil, it has been effective for both therapeutic and prophylactic uses (5Looareesuwan S. Chulay J.D. Canfield C.J. Hutchinson D.B. Am. J. Trop. Med. Hyg. 1999; 60: 533-541Crossref PubMed Scopus (173) Google Scholar, 6Ling J. Baird J.K. Fryauff D.J. Sismadi P. Bangs M.J. Lacy M. Barcus M.J. Gramzinski R. Maguire J.D. Kumusumangsih M. Miller G.B. Jones T.R. Chulay J.D. Hoffman S.L. Clin. Infect. Dis. 2002; 35: 825-833Crossref PubMed Scopus (78) Google Scholar, 7Lacy M.D. Maguire J.D. Barcus M.J. Ling J. Bangs M.J. Gramzinski R. Basri H. Sismadi P. Miller G.B. Chulay J.D. Fryauff D.J. Hoffman S.L. Baird J.K. Clin. Infect. Dis. 2002; 35: e92-e95Crossref PubMed Scopus (36) Google Scholar). On the other hand, once atovaquone resistance has arisen, the combination is no longer effective against malaria parasites (8Fivelman Q.L. Adagu I.S. Warhurst D.C. Antimicrob. Agents Chemother. 2004; 48: 4097-4102Crossref PubMed Scopus (224) Google Scholar, 9Srivastava I.K. Morrisey J.M. Darrouzet E. Daldal F. Vaidya A.B. Mol. Microbiol. 1999; 33: 704-711Crossref PubMed Scopus (253) Google Scholar). Previous studies have shown that atovaquone selectively inhibits mitochondrial electron transport in the parasite, consistent with the prevalent theory that hydroxynaphthoquinones function as ubiquinone antagonists (10Fry M. Pudney M. Biochem. Pharmacol. 1992; 43: 1545-1553Crossref PubMed Scopus (417) Google Scholar, 11Srivastava I.K. Rottenberg H. Vaidya A.B. J. Biol. Chem. 1997; 272: 3961-3966Abstract Full Text Full Text PDF PubMed Scopus (353) Google Scholar). Additionally, atovaquone was found to collapse the parasite mitochondrial membrane potential at nanomolar concentrations (11Srivastava I.K. Rottenberg H. Vaidya A.B. J. Biol. Chem. 1997; 272: 3961-3966Abstract Full Text Full Text PDF PubMed Scopus (353) Google Scholar), and its effect on the membrane potential is enhanced by synergistic activity of proguanil (12Srivastava I.K. Vaidya A.B. Antimicrob. Agents Chemother. 1999; 43: 1334-1339Crossref PubMed Google Scholar). To derive a better molecular understanding of the mode of action of atovaquone, a series of independently derived atovaquone-resistant malaria parasites were investigated (9Srivastava I.K. Morrisey J.M. Darrouzet E. Daldal F. Vaidya A.B. Mol. Microbiol. 1999; 33: 704-711Crossref PubMed Scopus (253) Google Scholar). All of the resistant parasite clones contained mutations in a specific, well conserved segment of the cytochrome b subunit of the cytochrome bc1 complex (ubihydroquinone-cytochrome c oxidoreductase), thus identifying a likely binding region within the ubihydroquinone oxidizing (Qo) 1The abbreviations used are: Qo, ubihydroquinone oxidation site; Qi, ubiquinone reduction site; [2Fe-2S], two iron-two sulfur (cluster). site of the malaria bc1 complex (9Srivastava I.K. Morrisey J.M. Darrouzet E. Daldal F. Vaidya A.B. Mol. Microbiol. 1999; 33: 704-711Crossref PubMed Scopus (253) Google Scholar). Similar mutations associated with atovaquone resistance have been identified in clinical isolates (13Fivelman Q.L. Butcher G.A. Adagu I.S. Warhurst D.C. Pasvol G. Malar. J. 2002; 1: 1Crossref PubMed Scopus (25) Google Scholar, 14Korsinczky M. Chen N. Kotecka B. Saul A. Rieckmann K. Cheng Q. Antimicrob. Agents Chemother. 2000; 44: 2100-2108Crossref PubMed Scopus (299) Google Scholar), as well as in experimental rodent malaria models (15Syafruddin D. Siregar J.E. Marzuki S. Mol. Biochem. Parasitol. 1999; 104: 185-194Crossref PubMed Scopus (83) Google Scholar). With mitochondrial electron transport having been validated as an important target for antimalarial drugs, it will be helpful to derive molecular details of atovaquone interactions with the cytochrome bc1 complex with the hope of exploring alternate compounds with antimalarial activity. Recent determinations of the structure of two examples of the vertebrate cytochrome bc1 complex (16Zhang Z. Huang L. Shulmeister V.M. Chi Y.I. Kim K.K. Hung L.W. Crofts A.R. Berry E.A. Kim S.H. Nature. 1998; 392: 677-684Crossref PubMed Scopus (948) Google Scholar, 17Kim H. Xia D. Yu C.A. Xia J.Z. Kachurin A.M. L. Yu L. J. S. A. 1998; PubMed Scopus Google Scholar), by those of C. J. C. H. 2000; Full Text Full Text PDF Scopus Google and the E.A. Huang M. Daldal F. 2004; PubMed Scopus Google Scholar), have the in the of this Because a large of experimental that the and of the complex well conserved in Biochem. PubMed Scopus Google Scholar, M. M. E. F. R. G. R. D. P. C. J. Mol. Biol. 2000; PubMed Scopus Google Scholar, E. Daldal F. 2004; PubMed Scopus Google Scholar, E.A. M. Huang Crofts A.R. Biochem. 2000; PubMed Scopus Google Scholar), we have to a relatively bacterial system to molecular details of the mode of action of atovaquone. The region in cytochrome b associated with atovaquone resistance a of the and bacterial R. the cytochrome bc1 complex of which to site-directed and its structure has been E.A. Huang M. Daldal F. 2004; PubMed Scopus Google Scholar). this bacterial it has been to an large domain movement involving the protein that electron transfer from ubihydroquinone within cytochrome b to cytochrome c1 E. M. P.L. Daldal F. S. A. 2000; PubMed Scopus Google Scholar, M. Darrouzet E. C.A. Daldal F. 2000; PubMed Scopus Google K. Yu L. Yu C.A. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, and this we have R. cytochrome b mutants predicted to have either enhanced or reduced sensitivity to atovaquone. of the cytochrome bc1 through biochemical and biophysical new the molecular mode of action of atovaquone as a antimalarial and were in in the of and R. in E. Daldal F. S. A. PubMed Scopus Google or in H. Microbiol. Scopus Google in the of or of R. was at in the or in is a cytochrome in which the of the has been and by a resistance to E. Daldal F. S. A. PubMed Scopus Google Scholar). The to in with the P.L. Daldal F. 33: PubMed Scopus Google Scholar), which is a that resistance to and a of were by mutagenesis in E. Daldal F. S. A. PubMed Scopus Google Scholar), either a as H. D. Daldal F. S. A. 1999; PubMed Scopus Google Scholar), or the system from with of the The used were the to the in and in a to a site as well as the target of the used in mutagenesis and on The of the the mutation thus was with its in and the were E. Daldal F. S. A. PubMed Scopus Google Scholar). the of the mutation and of mutation on the thus was by The cytochrome b was from a of the cytochrome bc1 complex. and membrane and protein were as E. Daldal F. S. A. PubMed Scopus Google Scholar), that protein determinations were in the of of c were as E. Daldal F. S. A. PubMed Scopus Google Scholar), at in a with a of cytochrome of and The reduction of cytochrome c was with a in mode experimental in the in this were from was by an of and were with with were to M. Darrouzet E. C.A. Daldal F. 2000; PubMed Scopus Google Scholar), in the of in of of and for at in 2 of and of or atovaquone, in a of were by with against the iron-sulfur protein of R. M. Darrouzet E. C.A. Daldal F. 2000; PubMed Scopus Google Scholar). were on a was by an with an The was with a the were as 2 and were with the ubiquinone and reduced by of were as E. M. P.L. Daldal F. S. A. 2000; PubMed Scopus Google Scholar, M. Z. Berry E.A. Daldal F. 1998; PubMed Scopus Google by and a single of in the of and cytochrome c by a from a was at The concentrations of atovaquone, and used were and and the potential was at of R. with a cytochrome bc1 complex is not required for of R. because of the of an alternate D. G. Daldal F. Microbiol. 1992; Scopus Google Scholar), this is for its in with a cytochrome bc1 complex, the efficiency of the cytochrome bc1 complex. the cytochrome b of Plasmodium and R. a conserved of the site of the ef the conserved which is to be in the binding of atovaquone (9Srivastava I.K. Morrisey J.M. Darrouzet E. Daldal F. Vaidya A.B. Mol. Microbiol. 1999; 33: 704-711Crossref PubMed Scopus (253) Google Scholar), we within the segment from to the and two Because atovaquone binding is likely by we the two R. and to Plasmodium and to better the structure of the malaria cytochrome bc1 complex in this to in both the and the This to the site most found in clinical cases of malaria atovaquone resistance (8Fivelman Q.L. Adagu I.S. Warhurst D.C. Antimicrob. Agents Chemother. 2004; 48: 4097-4102Crossref PubMed Scopus (224) Google Scholar, 14Korsinczky M. Chen N. Kotecka B. Saul A. Rieckmann K. Cheng Q. Antimicrob. Agents Chemother. 2000; 44: 2100-2108Crossref PubMed Scopus (299) Google Scholar). R. were for as well as for the activity of cytochrome bc1 complex in shown in the was reduced by of the in and but was reduced by in the from to cytochrome bc1 complex activity. The protein as well the and cytochrome of membrane were that produced and of cytochrome bc1 the The cytochrome bc1 complex activity was reduced in the but by in the atovaquone were consistent with the effect of the on of R. the of was lower than its effect on because of the of the cytochrome bc1 complex in a of R. and membrane of membrane other than the of b of of cytochrome c of activity of cytochrome c of membrane other than the The of activity of cytochrome c in a new of the bc1 by Atovaquone and of atovaquone, and on cytochrome bc1 complex activity in from the R. from the atovaquone shown in and the concentrations for the for each in The cytochrome bc1 complex was by atovaquone with of However, or F. E. M. J. PubMed Scopus Google Scholar), R. is not by atovaquone the drug is in the because of of to its site of action in bc1 complex from the the was by atovaquone with of This reduction in is consistent with our that in the Plasmodium cytochrome b responsible for the enhanced therapeutic for atovaquone. The to one in atovaquone-resistant human malaria increased the of atovaquone in the cytochrome bc1 complex. This was in both the and now a the of a conserved within the ef loop and of atovaquone resistance in malaria parasites. was to that the more on for two other site and it by with for atovaquone consistent with the binding of the two at the site L. B. M. M. Yu L. Yu C.A. Xia D. J. Mol. Biol. 2004; PubMed Scopus Google Scholar), and with the among the site in the of atovaquone, the the by site of site of membrane on of the of the the of the mutations that resistance to atovaquone, the for atovaquone well and the at concentrations of This to be to the of atovaquone in and the to the of at the on of the of the the of the mutations that resistance to atovaquone, the for atovaquone well and the at concentrations of This to be to the of atovaquone in and the to the of at the of membrane The on of the of the the of the mutations that resistance to atovaquone, the for atovaquone well and the at concentrations of This to be to the of atovaquone in and the to the of at the in a new of on the by of the is very to its molecular and to the at the site in cytochrome b H. D.E. Daldal F. P.L. 1992; PubMed Scopus Google Scholar). the this a relatively at a which is of the interactions of the reduced with ubiquinone in the site H. D.E. Daldal F. P.L. 1995; PubMed Scopus Google Scholar). to the of and mutations on the of and in were in the and of The of the cytochrome bc1 complex the is to lower and than that of the which be because of in the interactions of the with the site in the the of or atovaquone this to and to on the to in the of and H. D.E. Daldal F. P.L. 1992; PubMed Scopus Google Scholar, H. D.E. Daldal F. P.L. 1995; PubMed Scopus Google Scholar), that the site of the cytochrome bc1 complex the mutations is not in to the in the of atovaquone and the cytochrome bc1 complex, the is and than that with the suggesting that in this the interactions more the of the cytochrome bc1 the single and the mutations were with that of the were The and from to interactions the and the site and its the of or the two cytochrome bc1 the mutation a at the as those with atovaquone. in this region of the in the of or of A and suggesting in the of atovaquone, both of the cytochrome bc1 the mutation a at a of to that with the than the of the the that atovaquone has a and with the of the cytochrome bc1 complex the which is by the of the bc1 in the of cytochrome bc1 were in which the transfer of to cytochrome c a single of the the cytochrome c by an that in the which in cytochrome c which by the cytochrome bc1 The of and were with an of electron transfer from the in the of the E. M. P.L. Daldal F. S. A. 2000; PubMed Scopus Google and in the of and a involving of the by ubihydroquinone in the site and reduction of cytochrome c by the reduced The by the and the cytochrome bc1 to the of site blocks the of cytochrome c reduction by ubihydroquinone from the both of the by locking the at the cytochrome b E. M. P.L. Daldal F. S. A. 2000; PubMed Scopus Google Scholar). in both the and the cytochrome bc1 atovaquone both that it at the site in a to and both ubihydroquinone binding at the site by of the but has been shown to the large movement of the domain E. M. P.L. Daldal F. S. A. 2000; PubMed Scopus Google Scholar, M. Darrouzet E. C.A. Daldal F. 2000; PubMed Scopus Google required for electron transfer to cytochrome of Atovaquone on the of the the domain by was shown to be by sensitivity of the segment of the protein to by E. M. P.L. Daldal F. S. A. 2000; PubMed Scopus Google Scholar, M. Darrouzet E. C.A. Daldal F. 2000; PubMed Scopus Google Scholar), we the sensitivity of the cytochrome bc1 in the and of atovaquone, as well as and A. of with cytochrome bc1 resulted in of of the protein to the form from The of the form increased to in the of the site A. the of to the form was Atovaquone reduced the of the form but to a than with With the cytochrome bc1 complex the a of to the was but the in the of each the have found that the of to the form from to but the for each within an the in the and and largely the of both and A a in the of as M. Darrouzet E. C.A. Daldal F. 2000; PubMed Scopus Google Scholar), of and atovaquone reduced the of the sensitivity of the protein in the in the and of and atovaquone, to domain the of or atovaquone reduced the of the segment in the cytochrome bc1 complex to the of or atovaquone to the not from with at of cytochrome b, atovaquone and no longer to the of the R. has a as a system for the of the function of the cytochrome bc1 complex, a combination of and E. P.L. Daldal F. Biochem. Full Text Full Text PDF PubMed Scopus Google Scholar). with the use of identified the of cytochrome b that with the of the ubiquinone binding and Qi, to the of the structure of the cytochrome bc1 complex. Because atovaquone is a ubiquinone to which R. is relatively we have employed this well system to the molecular of the action of the The of of the region of the Plasmodium cytochrome b that was identified as a likely atovaquone site (9Srivastava I.K. Morrisey J.M. Darrouzet E. Daldal F. Vaidya A.B. Mol. Microbiol. 1999; 33: 704-711Crossref PubMed Scopus (253) Google with the region of the bacterial cytochrome the of the bacterial system for this two of the bacterial and were required to the of the segment in of the parasite cytochrome b that of the at which we found resistance mutations in a involving the of atovaquone-resistant Plasmodium parasites (9Srivastava I.K. Morrisey J.M. Darrouzet E. Daldal F. Vaidya A.B. Mol. Microbiol. 1999; 33: 704-711Crossref PubMed Scopus (253) Google Scholar). This segment the site of mutations in P. cytochrome b to in R. that have been with clinical resistance (8Fivelman Q.L. Adagu I.S. Warhurst D.C. Antimicrob. Agents Chemother. 2004; 48: 4097-4102Crossref PubMed Scopus (224) Google Scholar, 14Korsinczky M. Chen N. Kotecka B. Saul A. Rieckmann K. Cheng Q. Antimicrob. Agents Chemother. 2000; 44: 2100-2108Crossref PubMed Scopus (299) Google Scholar). and P. B. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, K. P. B. H. C. S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google have the cytochrome bc1 complex as a for and parasite the cytochrome b to be more to that of as than to that of parasites. we the increased the sensitivity of the bacterial cytochrome bc1 complex to atovaquone, but not to or This effect was a in the for atovaquone, as the complex is relatively to the for interactions with atovaquone, the biochemical and biophysical of the cytochrome bc1 complex were very to those of the complex. The activity in was reduced by and the to in the was to that of the The in the of the the cytochrome bc1 complex were in the of atovaquone, a and of the was in the The complex to the complex with to with in the and of a more atovaquone and the at the site of the cytochrome bc1 complex, which may the sensitivity of this complex to the the of the mutation in the R. cytochrome was by the experimental both the and the cytochrome b the by 2 of increased of atovaquone, were for and This was by a 10-fold of activity. The combination of reduced activity and reduced to atovaquone that the the of the cytochrome bc1 complex for the as well as for the atovaquone. The of with the this as the very in the of atovaquone, which is consistent with a reduced or of the with the the of the consistent with reduced of atovaquone with the The region of the protein of the cytochrome bc1 complex is to by but in the of the segment is a that is resistant to this we have shown that atovaquone the protein in the and from the of the atovaquone or from suggesting reduced or of The of the and the with the and cytochrome bc1 in the of of atovaquone to that of both the and of electron transfer to cytochrome and both from of the protein by the other site which has a different effect in of mammalian and cytochrome bc1 in the of or the protein is in a with its domain in with the ef loop region of cytochrome b, and its region in an form (16Zhang Z. Huang L. Shulmeister V.M. Chi Y.I. Kim K.K. Hung L.W. Crofts A.R. Berry E.A. Kim S.H. Nature. 1998; 392: 677-684Crossref PubMed Scopus (948) Google Scholar, 17Kim H. Xia D. Yu C.A. Xia J.Z. Kachurin A.M. L. Yu L. J. S. A. 1998; PubMed Scopus Google Scholar, C. J. C. H. 2000; Full Text Full Text PDF Scopus Google Scholar). This was found to be a which thus electron transfer to cytochrome the b in the site two in the ef loop of cytochrome b, which two of the subunit its a one of its and the of the of Atovaquone may in the site in a to with an from a or of the a with the of the K. P. B. H. C. S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google an of atovaquone in the site of cytochrome bc1 complex, which that the drug to the in this with a the and a of the in the interactions of atovaquone and with the cytochrome bc1 complex, as by in the and the that the mutation resistance to atovaquone, but has on that to an of the complex, it no longer against of the this we that the show that the in the binding site of C. J. C. H. 2000; Full Text Full Text PDF Scopus Google Scholar, L. B. M. M. Yu L. Yu C.A. Xia D. J. Mol. Biol. 2004; PubMed Scopus Google Scholar, A.R. M. R. N. J. S. 2000; PubMed Scopus Google Scholar). still to the complex, the of the domain of the protein subunit with the drug or the ef loop of cytochrome b to have been Plasmodium and R. as we have the cytochrome bc1 from both by atovaquone, vertebrate cytochrome bc1 The sensitivity of the and bacterial to atovaquone to with of in the ef loop of cytochrome b atovaquone is in the site of cytochrome bc1 the domain of the protein to be in a cytochrome b-binding conformation. electron transfer from the to cytochrome the of by atovaquone may be that of binding of atovaquone within the site binding of the binding may or electron transfer through its effect on the of the domain of the protein the interactions of atovaquone with the site may be different from those of as by the and it is that the mutation which is to a mutation associated with resistance to atovaquone in malaria has a on the interactions of atovaquone with the bacterial as The is over 2 of and the to the domain of the is The of the in the of atovaquone The the of other and the ubihydroquinone with the at the of the activity of the cytochrome bc1 complex. The direct of by site-directed mutagenesis in a system that the is the direct of resistance in the The mutation at the conserved to a cost on the efficiency of the bc1 complex. A mutation in the mitochondrial in the has been associated with a mitochondrial and activity in a F. K. M. N. J. PubMed Scopus Google Scholar). malaria parasites to have a in P. J.M. Chen N. M. M. S. Saul A. Cheng Q. Antimicrob. Agents Chemother. 2002; PubMed Scopus Google Scholar). from the the that atovaquone-resistant malaria parasites may have a and that of the drug may to of the resistant parasites with a as has been for parasites in B. T.E. J. Infect. Dis. PubMed Scopus Google Scholar).
No takes yet. Share an insight, caveat, or question.
Mather et al. (2005) studied this question.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: