ArticleAntimicrobial agents and chemotherapy2013
Cyclic AMP effectors in African trypanosomes revealed by genome-scale RNA interference library screening for resistance to the phosphodiesterase inhibitor CpdA.
Article in Antimicrobial agents and chemotherapy, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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43 citing papers in PubMed, 69 citations in OpenAlex.
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- Outlining the structure of cAMP compartments in Trypanosoma cruzi.Trends in parasitology · 2025Review
- Evolutionary analysis of the Leishmania major orthologues for the newly identified cyclic AMP response proteins.Archives of microbiology · 2025Article
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- Analysis of a Novel Peptide That Is Capable of Inhibiting the Enzymatic Activity of the Protein Kinase A Catalytic Subunit-Like Protein from Trypanosoma equiperdum.The protein journal · 2023Article
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- Tackling Sleeping Sickness: Current and Promising Therapeutics and Treatment Strategies.International journal of molecular sciences · 2023Review
- Cell-cell communication in African trypanosomes.Microbiology (Reading, England) · 2023Review
- In silico evolutionary and structural analysis of cAMP response proteins (CARPs) from Leishmania major.Archives of microbiology · 2023Article
- Novel kinetoplastid-specific cAMP binding proteins identified by RNAi screening for cAMP resistance inFrontiers in cellular and infection microbiology · 2023Article
- A multi-adenylate cyclase regulator at the flagellar tip controls African trypanosome transmission.Nature communications · 2022Article
- Cyclic AMP signalling and glucose metabolism mediate pH taxis by African trypanosomes.Nature communications · 2022Article
- APEX2 Proximity Proteomics Resolves Flagellum Subdomains and Identifies Flagellum Tip-Specific Proteins in Trypanosoma brucei.mSphere · 2021Article
- Large-Scale Phylogenetic Analysis of Trypanosomatid Adenylate Cyclases Reveals Associations with Extracellular Lifestyle and Host-Pathogen Interplay.Genome biology and evolution · 2020Article
- Cloning and functional complementation of ten Schistosoma mansoni phosphodiesterases expressed in the mammalian host stages.PLoS neglected tropical diseases · 2020Article
- Experimental Strategies to Explore Drug Action and Resistance in Kinetoplastid Parasites.Microorganisms · 2020Review
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Authors and funding
10 authors at 5 institutions in 2 countries.
Funding
Abstract
One of the most promising new targets for trypanocidal drugs to emerge in recent years is the cyclic AMP (cAMP) phosphodiesterase (PDE) activity encoded by TbrPDEB1 and TbrPDEB2. These genes were genetically confirmed as essential, and a high-affinity inhibitor, CpdA, displays potent antitrypanosomal activity. To identify effectors of the elevated cAMP levels resulting from CpdA action and, consequently, potential sites for adaptations giving resistance to PDE inhibitors, resistance to the drug was induced. Selection of mutagenized trypanosomes resulted in resistance to CpdA as well as cross-resistance to membrane-permeable cAMP analogues but not to currently used trypanocidal drugs. Resistance was not due to changes in cAMP levels or in PDEB genes. A second approach, a genome-wide RNA interference (RNAi) library screen, returned four genes giving resistance to CpdA upon knockdown. Validation by independent RNAi strategies confirmed resistance to CpdA and suggested a role for the identified cAMP Response Proteins (CARPs) in cAMP action. CARP1 is unique to kinetoplastid parasites and has predicted cyclic nucleotide binding-like domains, and RNAi repression resulted in >100-fold resistance. CARP2 and CARP4 are hypothetical conserved proteins associated with the eukaryotic flagellar proteome or with flagellar function, with an orthologue of CARP4 implicated in human disease. CARP3 is a hypothetical protein, unique to Trypanosoma. CARP1 to CARP4 likely represent components of a novel cAMP signaling pathway in the parasite. As cAMP metabolism is validated as a drug target in Trypanosoma brucei, cAMP effectors highly divergent from the mammalian host, such as CARP1, lend themselves to further pharmacological development.
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