PMID- 23877697
OWN - NLM
STAT- MEDLINE
DCOM- 20140409
LR  - 20231115
IS  - 1098-6596 (Electronic)
IS  - 0066-4804 (Print)
IS  - 0066-4804 (Linking)
VI  - 57
IP  - 10
DP  - 2013 Oct
TI  - Cyclic AMP effectors in African trypanosomes revealed by genome-scale RNA 
      interference library screening for resistance to the phosphodiesterase inhibitor 
      CpdA.
PG  - 4882-93
LID - 10.1128/AAC.00508-13 [doi]
AB  - 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.
FAU - Gould, Matthew K
AU  - Gould MK
AD  - Institute of Infection, Immunity & Inflammation, College of Medical, Veterinary & 
      Life Sciences, University of Glasgow, Glasgow, United Kingdom.
FAU - Bachmaier, Sabine
AU  - Bachmaier S
FAU - Ali, Juma A M
AU  - Ali JA
FAU - Alsford, Sam
AU  - Alsford S
FAU - Tagoe, Daniel N A
AU  - Tagoe DN
FAU - Munday, Jane C
AU  - Munday JC
FAU - Schnaufer, Achim C
AU  - Schnaufer AC
FAU - Horn, David
AU  - Horn D
FAU - Boshart, Michael
AU  - Boshart M
FAU - de Koning, Harry P
AU  - de Koning HP
LA  - eng
GR  - 085349/WT_/Wellcome Trust/United Kingdom
GR  - G0600129/MRC_/Medical Research Council/United Kingdom
GR  - 093010/Z/10/Z/WT_/Wellcome Trust/United Kingdom
GR  - 095831/WT_/Wellcome Trust/United Kingdom
GR  - G0701258/MRC_/Medical Research Council/United Kingdom
GR  - WT_/Wellcome Trust/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130722
PL  - United States
TA  - Antimicrob Agents Chemother
JT  - Antimicrobial agents and chemotherapy
JID - 0315061
RN  - 0 (Phosphodiesterase Inhibitors)
RN  - 0 (Protozoan Proteins)
RN  - 0 (Trypanocidal Agents)
RN  - E0399OZS9N (Cyclic AMP)
SB  - IM
MH  - Blotting, Western
MH  - Cyclic AMP/*metabolism
MH  - Phosphodiesterase Inhibitors/*pharmacology
MH  - Polymerase Chain Reaction
MH  - Protozoan Proteins/genetics/metabolism
MH  - RNA Interference
MH  - Trypanocidal Agents/*pharmacology
MH  - Trypanosoma brucei brucei/*drug effects/genetics/*metabolism
PMC - PMC3811416
EDAT- 2013/07/24 06:00
MHDA- 2014/04/10 06:00
PMCR- 2013/10/01
CRDT- 2013/07/24 06:00
PHST- 2013/07/24 06:00 [entrez]
PHST- 2013/07/24 06:00 [pubmed]
PHST- 2014/04/10 06:00 [medline]
PHST- 2013/10/01 00:00 [pmc-release]
AID - AAC.00508-13 [pii]
AID - 00508-13 [pii]
AID - 10.1128/AAC.00508-13 [doi]
PST - ppublish
SO  - Antimicrob Agents Chemother. 2013 Oct;57(10):4882-93. doi: 10.1128/AAC.00508-13. 
      Epub 2013 Jul 22.