Resistance mutations reveal the atovaquone-binding domain of cytochrome b in malaria parasites.


:Atovaquone represents a class of antimicrobial agents with a broad-spectrum activity against various parasitic infections, including malaria, toxoplasmosis and Pneumocystis pneumonia. In malaria parasites, atovaquone inhibits mitochondrial electron transport at the level of the cytochrome bc1 complex and collapses mitochondrial membrane potential. In addition, this drug is unique in being selectively toxic to parasite mitochondria without affecting the host mitochondrial functions. A better understanding of the structural basis for the selective toxicity of atovaquone could help in designing drugs against infections caused by mitochondria-containing parasites. To that end, we derived nine independent atovaquone-resistant malaria parasite lines by suboptimal treatment of mice infected with Plasmodium yoelii; these mutants exhibited resistance to atovaquone-mediated collapse of mitochondrial membrane potential as well as inhibition of electron transport. The mutants were also resistant to the synergistic effects of atovaquone/ proguanil combination. Sequencing of the mitochondrially encoded cytochrome b gene placed these mutants into four categories, three with single amino acid changes and one with two adjacent amino acid changes. Of the 12 nucleotide changes seen in the nine independently derived mutants 11 replaced A:T basepairs with G:C basepairs, possibly because of reactive oxygen species resulting from atovaquone treatment. Visualization of the resistance-conferring amino acid positions on the recently solved crystal structure of the vertebrate cytochrome bc1 complex revealed a discrete cavity in which subtle variations in hydrophobicity and volume of the amino acid side-chains may determine atovaquone-binding affinity, and thereby selective toxicity. These structural insights may prove useful in designing agents that selectively affect cytochrome bc1 functions in a wide range of eukaryotic pathogens.


Mol Microbiol


Molecular microbiology


Srivastava IK,Morrisey JM,Darrouzet E,Daldal F,Vaidya AB




Has Abstract


1999-08-01 00:00:00














  • Phosphatases modulate the bistable sporulation gene expression pattern in Bacillus subtilis.

    abstract::Summary Spore formation in the Gram-positive bacterium Bacillus subtilis is a last resort adaptive response to starvation. To initiate sporulation, the key regulator in this process, Spo0A, needs to be activated by the so-called phosphorelay. Within a sporulating culture of B. subtilis, some cells initiate this develo...

    journal_title:Molecular microbiology

    pub_type: 杂志文章


    authors: Veening JW,Hamoen LW,Kuipers OP

    更新日期:2005-06-01 00:00:00

  • Differential Flo8p-dependent regulation of FLO1 and FLO11 for cell-cell and cell-substrate adherence of S. cerevisiae S288c.

    abstract::Cell-cell and cell-surface adherence represents initial steps in forming multicellular aggregates or in establishing cell-surface interactions. The commonly used Saccharomyces cerevisiae laboratory strain S288c carries a flo8 mutation, and is only able to express the flocculin-encoding genes FLO1 and FLO11, when FLO8 ...

    journal_title:Molecular microbiology

    pub_type: 杂志文章


    authors: Fichtner L,Schulze F,Braus GH

    更新日期:2007-12-01 00:00:00

  • The pAM beta 1 CopF repressor regulates plasmid copy number by controlling transcription of the repE gene.

    abstract::pAM beta 1 is a low-copy-number, promiscuous plasmid from Gram-positive bacteria that replicates by a unidirectional theta-type mode. Its replication is initiated by an original mechanism, involving the positive rate-limiting RepE protein. Here we show that the pAM beta 1-encoded CopF protein is involved in negative r...

    journal_title:Molecular microbiology

    pub_type: 杂志文章


    authors: Le Chatelier E,Ehrlich SD,Jannière L

    更新日期:1994-11-01 00:00:00

  • Coupling of Escherichia coli hns mRNA levels to DNA synthesis by autoregulation: implications for growth phase control.

    abstract::The H-NS protein of enteric bacteria is one of the major proteins of the bacterial nucleoid and seems to play an important role in nucleoid structure. Transcription of the hns gene encoding the H-NS protein appears to be negatively regulated by H-NS itself both in vitro and in vivo. We have examined the role of this m...

    journal_title:Molecular microbiology

    pub_type: 杂志文章


    authors: Free A,Dorman CJ

    更新日期:1995-10-01 00:00:00

  • The involvement of NAD(P)H dehydrogenase subunits, NdhD3 and NdhF3, in high-affinity CO2 uptake in Synechococcus sp. PCC7002 gives evidence for multiple NDH-1 complexes with specific roles in cyanobacteria.

    abstract::Random gene tagging was used to obtain new mutants of the marine cyanobacterium, Synechococcus sp. PCC7002, with defects in the CO2-concentrating mechanism (CCM). Two of these mutants, K22 and A41, showed poor growth at limiting CO2. Isolation and sequencing of a 6. 6 kb genomic region revealed the existence of five p...

    journal_title:Molecular microbiology

    pub_type: 杂志文章


    authors: Klughammer B,Sültemeyer D,Badger MR,Price GD

    更新日期:1999-06-01 00:00:00

  • A member of the cAMP receptor protein family of transcription regulators in Mycobacterium tuberculosis is required for virulence in mice and controls transcription of the rpfA gene coding for a resuscitation promoting factor.

    abstract::Deletion of gene Rv3676 in Mycobacterium tuberculosis coding for a transcription factor belonging to the cAMP receptor protein (CRP) family caused growth defects in laboratory medium, in bone marrow-derived macrophages and in a mouse model of tuberculosis. Transcript profiling of M. tuberculosis grown in vitro identif...

    journal_title:Molecular microbiology

    pub_type: 杂志文章


    authors: Rickman L,Scott C,Hunt DM,Hutchinson T,Menéndez MC,Whalan R,Hinds J,Colston MJ,Green J,Buxton RS

    更新日期:2005-06-01 00:00:00

  • The divisomal protein DivIB contains multiple epitopes that mediate its recruitment to incipient division sites.

    abstract::Bacterial cytokinesis is orchestrated by an assembly of essential cell division proteins that form a supramolecular structure known as the divisome. DivIB and its orthologue FtsQ are essential members of the divisome in Gram-positive and Gram-negative bacteria respectively. DivIB is a bitopic membrane protein composed...

    journal_title:Molecular microbiology

    pub_type: 杂志文章


    authors: Wadsworth KD,Rowland SL,Harry EJ,King GF

    更新日期:2008-03-01 00:00:00

  • Two essential FtsH proteases control the level of the Fur repressor during iron deficiency in the cyanobacterium Synechocystis sp. PCC 6803.

    abstract::The cyanobacterium Synechocystis sp. PCC 6803 expresses four different FtsH protease subunits (FtsH1-4) that assemble into specific homo- and heterocomplexes. The FtsH2/FtsH3 complex is involved in photoprotection but the physiological roles of the other complexes, notably the essential FtsH1/FtsH3 complex, remain unc...

    journal_title:Molecular microbiology

    pub_type: 杂志文章


    authors: Krynická V,Tichý M,Krafl J,Yu J,Kaňa R,Boehm M,Nixon PJ,Komenda J

    更新日期:2014-11-01 00:00:00

  • Socializing, networking and development: a report from the second 'Young Microbiologists Symposium on Microbe Signalling, Organization and Pathogenesis'.

    abstract::In mid-June, the second Young Microbiologists Symposium took place under the broad title of 'Microbe signalling, organization and pathogenesis' on the picturesque campus of University College Cork, Ireland. The symposium attracted 150 microbiologists from 15 different countries. The key feature of this meeting was tha...

    journal_title:Molecular microbiology



    authors: Caly DL,Coulthurst SJ,Geoghegan JA,Malone JG,Ryan RP

    更新日期:2012-11-01 00:00:00

  • Isolation and characterization of the secE homologue gene of Bacillus subtilis.

    abstract::A 4.0 kb EcoRI fragment of Bacillus subtilis conferring thiostrepton resistance was cloned and characterized. By nucleotide sequencing of the relevant region, six open reading frames were established, which corresponded to a part of spo0H, a ribosomal protein gene (rpmG), an unidentified open reading frame (orfE), a t...

    journal_title:Molecular microbiology

    pub_type: 杂志文章


    authors: Jeong SM,Yoshikawa H,Takahashi H

    更新日期:1993-10-01 00:00:00

  • FbpA, a novel multifunctional Listeria monocytogenes virulence factor.

    abstract::Listeria monocytogenes is a Gram-positive intracellular bacterium responsible for severe opportunistic infections in humans and animals. Signature-tagged mutagenesis (STM) was used to identify a gene named fbpA, required for efficient liver colonization of mice inoculated intravenously. FbpA was also shown to be requi...

    journal_title:Molecular microbiology

    pub_type: 杂志文章


    authors: Dramsi S,Bourdichon F,Cabanes D,Lecuit M,Fsihi H,Cossart P

    更新日期:2004-07-01 00:00:00

  • Structure and function of DnaA and the DnaA-box in eubacteria: evolutionary relationships of bacterial replication origins.

    abstract::DnaA protein (a trans-acting element) and its binding sequence, DnaA-box: (a cis-acting element) are two elements essential for the initiation of chromosomal replication in Escherichia coli and other enteric bacteria. Recently these two elements have been found to be conserved in three Gram-positive bacteria (Bacillus...

    journal_title:Molecular microbiology

    pub_type: 杂志文章,评审


    authors: Yoshikawa H,Ogasawara N

    更新日期:1991-11-01 00:00:00

  • A recently isolated human commensal Escherichia coli ST10 clone member mediates enhanced thermotolerance and tetrathionate respiration on a P1 phage-derived IncY plasmid.

    abstract::The ubiquitous human commensal Escherichia coli has been well investigated through its model representative E. coli K-12. In this work, we initially characterized E. coli Fec10, a recently isolated human commensal strain of phylogroup A/sequence type ST10. Compared to E. coli K-12, the 4.88 Mbp Fec10 genome is charact...

    journal_title:Molecular microbiology

    pub_type: 杂志文章


    authors: Kamal SM,Cimdins-Ahne A,Lee C,Li F,Martín-Rodríguez AJ,Seferbekova Z,Afasizhev R,Wami HT,Katikaridis P,Meins L,Lünsdorf H,Dobrindt U,Mogk A,Römling U

    更新日期:2020-09-28 00:00:00

  • Structural and transcriptional analysis of the pyrABCN, pyrD and pyrF genes in Aspergillus nidulans and the evolutionary origin of fungal dihydroorotases.

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    journal_title:Molecular microbiology

    pub_type: 杂志文章


    authors: Aleksenko A,Liu W,Gojkovic Z,Nielsen J,Piskur J

    更新日期:1999-08-01 00:00:00

  • Escherichia coli DNA glycosylase Mug: a growth-regulated enzyme required for mutation avoidance in stationary-phase cells.

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    journal_title:Molecular microbiology

    pub_type: 杂志文章


    authors: Mokkapati SK,Fernández de Henestrosa AR,Bhagwat AS

    更新日期:2001-09-01 00:00:00

  • Generalized approach to the regulation and integration of gene expression.

    abstract::The volume of electron flow through the cbb3 branch of the electron transport chain and the redox state of the quinone pool generate signals that regulate photosynthesis gene expression in Rhodobacter sphaeroides. An inhibitory signal is generated at the level of the catalytic subunit of the cbb3 cytochrome c oxidase ...

    journal_title:Molecular microbiology

    pub_type: 杂志文章,评审


    authors: Oh JI,Kaplan S

    更新日期:2001-03-01 00:00:00

  • Characterization of a five-gene cluster required for the biogenesis of type 4 fimbriae in Pseudomonas aeruginosa.

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    journal_title:Molecular microbiology

    pub_type: 杂志文章


    authors: Martin PR,Watson AA,McCaul TF,Mattick JS

    更新日期:1995-05-01 00:00:00

  • Isolated DNA repeat region from fcrA76, the Fc-binding protein gene from an M-type 76 strain of group A streptococci, encodes a protein with Fc-binding activity.

    abstract::The DNA repeat region of fcrA76, the gene encoding a group A streptococcal Fc-binding protein, was subcloned in-frame into an Escherichia coli plasmid expression vector. The expressed protein product displayed the same Fc-binding properties as the full-length Fc-binding protein expressed from fcrA76. The affinity-puri...

    journal_title:Molecular microbiology

    pub_type: 杂志文章


    authors: Heath DG,Boyle MD,Cleary PP

    更新日期:1990-12-01 00:00:00

  • Multiple modes of iron uptake by the filamentous, siderophore-producing cyanobacterium, Anabaena sp. PCC 7120.

    abstract::Iron is a member of a small group of nutrients that limits aquatic primary production. Mechanisms for utilizing iron have to be efficient and adapted according to the ecological niche. In respect to iron acquisition cyanobacteria, prokaryotic oxygen evolving photosynthetic organisms can be divided into siderophore- an...

    journal_title:Molecular microbiology

    pub_type: 杂志文章


    authors: Rudolf M,Kranzler C,Lis H,Margulis K,Stevanovic M,Keren N,Schleiff E

    更新日期:2015-08-01 00:00:00

  • Mutagenesis, cloning and complementation analysis of C4-dicarboxylate transport genes from Rhodobacter capsulatus.

    abstract::Transposon mutagenesis was used to isolate insertion mutants of the photosynthetic bacterium Rhodobacter capsulatus which were unable to grow under aerobic conditions in the dark on malate, succinate or fumarate as sole carbon sources. Of five mutants isolated, all were deficient in C4-dicarboxylate transport. However...

    journal_title:Molecular microbiology

    pub_type: 杂志文章


    authors: Hamblin MJ,Shaw JG,Curson JP,Kelly DJ

    更新日期:1990-09-01 00:00:00

  • Topographic analysis of the toxic Gef protein from Escherichia coli.

    abstract::The chromosomal gef gene of Escherichia coli is a member of the gef gene family which encodes strongly toxic proteins of about 50 amino acids. We demonstrate here that the Gef protein is detectable by anti-peptide antibodies. Furthermore, we show that Gef is anchored in the cytoplasmic membrane by the N-terminal part ...

    journal_title:Molecular microbiology

    pub_type: 杂志文章


    authors: Poulsen LK,Refn A,Molin S,Andersson P

    更新日期:1991-07-01 00:00:00

  • Host-dependent requirement for specific DnaA boxes for plasmid RK2 replication.

    abstract::The replication origin of the broad-host-range plasmid RK2, oriV, contains four DnaA boxes, which bind the DnaA protein isolated from Escherichia coli. Using a transformation assay, mutational analysis of these boxes showed a differential requirement for replication in different Gram-negative bacteria. DnaA boxes 3 an...

    journal_title:Molecular microbiology

    pub_type: 杂志文章


    authors: Doran KS,Helinski DR,Konieczny I

    更新日期:1999-08-01 00:00:00

  • How does the oxidative burst of macrophages kill bacteria? Still an open question.

    abstract::Reactive oxygen species (ROS) are critical components of the antimicrobial repertoire of macrophages, yet the mechanisms by which ROS damage bacteria in the phagosome are unclear. The NADH-dependent phagocytic oxidase produces superoxide, which dismutes to form H(2)O(2). The Barras and Méresse labs use a GFP fusion to...

    journal_title:Molecular microbiology

    pub_type: 评论,杂志文章


    authors: Slauch JM

    更新日期:2011-05-01 00:00:00

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    journal_title:Molecular microbiology

    pub_type: 杂志文章


    authors: Pourjaberi SNS,Terahara N,Namba K,Minamino T

    更新日期:2017-11-01 00:00:00

  • Studies on the structure and function of the N-terminal domain of the pneumococcal murein hydrolases.

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    journal_title:Molecular microbiology

    pub_type: 杂志文章


    authors: Sanz JM,Díaz E,García JL

    更新日期:1992-04-01 00:00:00

  • Magnesium depletion triggers production of an immune modulating diterpenoid in Mycobacterium tuberculosis.

    abstract::Mycobacterium tuberculosis (Mtb) is the causative agent of the human disease Tuberculosis, and remains a worldwide health threat responsible for ∼1.7 million deaths annually. During infection, Mtb prevents acidification of the engulfing phagosome, thus blocking endocytic progression and eventually leading to stable re...

    journal_title:Molecular microbiology

    pub_type: 杂志文章


    authors: Mann FM,VanderVen BC,Peters RJ

    更新日期:2011-03-01 00:00:00

  • Four signalling domains in the hybrid histidine protein kinase RodK of Myxococcus xanthus are required for activity.

    abstract::In prokaryotes, the principal signal transduction systems operating at the level of protein phosphorylation are the two-component systems. A number of hybrid histidine protein kinases in these systems contain several receiver domains, however, the function of these receiver domains is unknown. The RodK kinase in Myxoc...

    journal_title:Molecular microbiology

    pub_type: 杂志文章


    authors: Rasmussen AA,Wegener-Feldbrügge S,Porter SL,Armitage JP,Søgaard-Andersen L

    更新日期:2006-04-01 00:00:00

  • Independent evolutionary origins of functional polyamine biosynthetic enzyme fusions catalysing de novo diamine to triamine formation.

    abstract::We have identified gene fusions of polyamine biosynthetic enzymes S-adenosylmethionine decarboxylase (AdoMetDC, speD) and aminopropyltransferase (speE) orthologues in diverse bacterial phyla. Both domains are functionally active and we demonstrate the novel de novo synthesis of the triamine spermidine from the diamine...

    journal_title:Molecular microbiology

    pub_type: 杂志文章


    authors: Green R,Hanfrey CC,Elliott KA,McCloskey DE,Wang X,Kanugula S,Pegg AE,Michael AJ

    更新日期:2011-08-01 00:00:00

  • A hierarchical quorum-sensing system in Yersinia pseudotuberculosis is involved in the regulation of motility and clumping.

    abstract::In cell-free Yersinia pseudotuberculosis culture supernatants, we have chemically characterized three N-acyl homoserine lactone (AHL) molecules, N-octanoyl homoserine lactone (C8-HSL), N-(3-oxohexanoyl)homoserine lactone (3-oxo-C6-HSL) and N-hexanoyl homoserine lactone (C6-HSL). We have identified, cloned and sequence...

    journal_title:Molecular microbiology

    pub_type: 杂志文章


    authors: Atkinson S,Throup JP,Stewart GS,Williams P

    更新日期:1999-09-01 00:00:00

  • Autoregulation of ZEB2 expression for zearalenone production in Fusarium graminearum.

    abstract::Several Fusarium species produce the polyketide mycotoxin zearalenone (ZEA), a causative agent of hyperestrogenic syndrome in animals that is often found in F. graminearum-infected cereals in temperate regions. The ZEA biosynthetic cluster genes PKS4, PKS13, ZEB1 and ZEB2 encode a reducing polyketide synthase, a non-r...

    journal_title:Molecular microbiology

    pub_type: 杂志文章


    authors: Park AR,Son H,Min K,Park J,Goo JH,Rhee S,Chae SK,Lee YW

    更新日期:2015-09-01 00:00:00