Parallel inhibition of amino acid efflux and growth of erythrocytic Plasmodium falciparum by mefloquine and non-piperidine analogs: Implication for the mechanism of antimalarial action

One approach to identify epitopes that could be used in the design of vaccines to control several arthropod-borne diseases simultaneously is to look for common structural features in the secretome of the pathogens that cause them. Using a novel bioinformatics technique, cysteine-abundance and distribution analysis, we found that many different proteins secreted by several arthropod-borne pathogens, includingPlasmodium falciparum, Borrelia burgdorferi, and eight species of Proteobacteria, are devoid of cysteine residues. The identification of three cysteine-abundance and distribution patterns in several families of proteins secreted by pathogenic and nonpathogenic Proteobacteria, and not found when the amino acid analyzed was tryptophan, provides evidence of forces restricting the content of cysteine residues in microbial proteins during evolution. We discuss these findings in the context of protein structure and function, antigenicity and immunogenicity, and host-parasite relationships.

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Multiple Antibiotics Exert Delayed Effects against the Plasmodium falciparum Apicoplast

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00527-07 ◽

2007 ◽

Vol 51 (10) ◽

pp. 3485-3490 ◽

Cited By ~ 184

Author(s):

Erica L. Dahl ◽

Philip J. Rosenthal

Keyword(s):

Plasmodium Falciparum ◽

Cell Division ◽

Antimalarial Activity ◽

Mechanisms Of Action ◽

Malaria Parasites ◽

Delayed Effects ◽

Delayed Death ◽

Antimalarial Action ◽

Multiple Antibiotics

ABSTRACT Several classes of antibiotics exert antimalarial activity. The mechanisms of action of antibiotics against malaria parasites have been unclear, and prior studies have led to conflicting results, in part because they studied antibiotics at suprapharmacological concentrations. We examined the antimalarial effects of azithromycin, ciprofloxacin, clindamycin, doxycycline, and rifampin against chloroquine-resistant (W2) and chloroquine-sensitive (3D7) Plasmodium falciparum strains. At clinically relevant concentrations, rifampin killed parasites quickly, preventing them from initiating cell division. In contrast, pharmacological concentrations of azithromycin, ciprofloxacin, clindamycin, and doxycycline were relatively inactive against parasites initially but exerted a delayed death effect, in which the progeny of treated parasites failed to complete erythrocytic development. The drugs that caused delayed death did not alter the distribution of apicoplasts into developing progeny. However, the apicoplasts inherited by the progeny of treated parasites were abnormal. The loss of apicoplast function became apparent as the progeny of antibiotic-treated parasites initiated cell division, with the failure of schizonts to fully mature or for erythrocyte rupture to take place. These findings explain the slow antimalarial action of multiple antibiotics.

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Structural and antigenic polymorphism of the 35- to 48-kilodalton merozoite surface antigen (MSA-2) of the malaria parasite Plasmodium falciparum

Molecular and Cellular Biology ◽

10.1128/mcb.11.2.963-971.1991 ◽

1991 ◽

Vol 11 (2) ◽

pp. 963-971

Author(s):

B Fenton ◽

J T Clark ◽

C M Khan ◽

J V Robinson ◽

D Walliker ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Amino Acid ◽

Surface Antigen ◽

Dna Sequences ◽

Amino Acid Sequences ◽

Merozoite Surface Antigen ◽

Parasite Plasmodium ◽

Genes Encoding ◽

Parasite Plasmodium Falciparum ◽

Group B

Merozoite surface antigen MSA-2 of the human parasite Plasmodium falciparum is being considered for the development of a malaria vaccine. The antigen is polymorphic, and specific monoclonal antibodies differentiate five serological variants of MSA-2 among 25 parasite isolates. The variants are grouped into two major serogroups, A and B. Genes encoding two different variants from serogroup A have been sequenced, and their DNA together with deduced amino acid sequences were compared with sequences encoded by other alleles. The comparison shows that the serological classification reflects differences in DNA sequences and deduced primary structure of MSA-2 variants and serogroups. Thus, the overall homologies of DNA and amino acid sequences are over 95% among variants in the same serogroup. In contrast, similarities between the group A variants and a group B variant are only 70 and 64% for DNA and amino acid sequences, respectively. We propose that the MSA-2 protein is encoded by two highly divergent groups of alleles, with limited additional polymorphism displayed within each group.

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The Biochemical Basis for the Selective Antimalarial Action of Iron Chelators on Plasmodium Falciparum Parasitized Cells

Advances in Experimental Medicine and Biology - Progress in Iron Research ◽

10.1007/978-1-4615-2554-7_40 ◽

1994 ◽

pp. 385-397 ◽

Cited By ~ 4

Author(s):

S. D. Lytton ◽

M. Loyevsky ◽

J. Libman ◽

B. Mester ◽

A. Shanzer ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Iron Chelators ◽

Biochemical Basis ◽

Antimalarial Action

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Volume-sensitive amino acid efflux from a pancreatic β-cell line

Molecular and Cellular Endocrinology ◽

10.1016/s0303-7207(99)00260-9 ◽

2000 ◽

Vol 162 (1-2) ◽

pp. 201-208 ◽

Cited By ~ 6

Author(s):

A.C.G. Grant ◽

J. Thomson ◽

V.A. Zammit ◽

D.B. Shennan

Keyword(s):

Amino Acid ◽

Cell Line ◽

Pancreatic Β Cell ◽

Β Cell ◽

Amino Acid Efflux

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Cloning of a Ca(2+)-ATPase gene of Plasmodium falciparum and comparison with vertebrate Ca(2+)-ATPases

Journal of Cell Science ◽

10.1242/jcs.104.4.1129 ◽

1993 ◽

Vol 104 (4) ◽

pp. 1129-1136 ◽

Cited By ~ 1

Author(s):

M. Kimura ◽

Y. Yamaguchi ◽

S. Takada ◽

K. Tanabe

Keyword(s):

Plasmodium Falciparum ◽

Plasma Membrane ◽

Amino Acid ◽

Amino Acid Sequence ◽

Phosphorylation Site ◽

Genomic Libraries ◽

Atpase Gene ◽

Binding Regions ◽

Cloned Gene ◽

Falciparum Protein

A Ca(2+)-ATPase gene was cloned from the genomic libraries of Plasmodium falciparum. From the deduced amino acid sequence of the gene, a 139 kDa protein with a total of 1228 amino acids was predicted. Sequence of a partial cDNA clone of the gene identified two introns near the 3′-end at the regions identical to the regions assumed for the Ca(2+)-ATPase gene of P. yoelii, a rodent malaria species. As compared with a variety of Ca(2+)-ATPases, the P. falciparum Ca(2+)-ATPase had the highest amino acid sequence homology (78%) to the P. yoelii Ca(2+)-ATPase, moderate homology (45-50%) to vertebrate sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPases (SERCAs), and lowest homology (20%) to a plasma membrane Ca(2+)-ATPase. The P. falciparum protein conserved sequences and residues that are important for the function and/or structure of the organellar type Ca(2+)-ATPase, such as high affinity Ca(2+)-binding sites, fluorescein isothiocyanate (FITC)-binding regions, and the phosphorylation site, but the protein did not contain calmodulin-binding regions that occur in the plasma membrane type Ca(2+)-ATPase. Thus we concluded the cloned gene was the organellar type Ca(2+)-ATPase of P. falciparum. In a region between the phosphorylation site and FITC-binding region, the P. falciparum protein was about 200 residues longer than the rabbit SERCA and lacked a sequence that binds to phospholamban, a protein that regulates the activity of the rabbit SERCA.(ABSTRACT TRUNCATED AT 250 WORDS)

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