• Je něco špatně v tomto záznamu ?

Trypanocidal action of bisphosphonium salts through a mitochondrial target in bloodstream form Trypanosoma brucei

AA. Alkhaldi, J. Martinek, B. Panicucci, C. Dardonville, A. Zíková, HP. de Koning,

. 2016 ; 6 (1) : 23-34. [pub] 20151211

Jazyk angličtina Země Anglie, Velká Británie

Typ dokumentu časopisecké články, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc17000293

Lipophilic bisphosphonium salts are among the most promising antiprotozoal leads currently under investigation. As part of their preclinical evaluation we here report on their mode of action against African trypanosomes, the etiological agents of sleeping sickness. The bisphosphonium compounds CD38 and AHI-9 exhibited rapid inhibition of Trypanosoma brucei growth, apparently the result of cell cycle arrest that blocked the replication of mitochondrial DNA, contained in the kinetoplast, thereby preventing the initiation of S-phase. Incubation with either compound led to a rapid reduction in mitochondrial membrane potential, and ATP levels decreased by approximately 50% within 1 h. Between 4 and 8 h, cellular calcium levels increased, consistent with release from the depolarized mitochondria. Within the mitochondria, the Succinate Dehydrogenase complex (SDH) was investigated as a target for bisphosphonium salts, but while its subunit 1 (SDH1) was present at low levels in the bloodstream form trypanosomes, the assembled complex was hardly detectable. RNAi knockdown of the SDH1 subunit produced no growth phenotype, either in bloodstream or in the procyclic (insect) forms and we conclude that in trypanosomes SDH is not the target for bisphosphonium salts. Instead, the compounds inhibited ATP production in intact mitochondria, as well as the purified F1 ATPase, to a level that was similar to 1 mM azide. Co-incubation with azide and bisphosphonium compounds did not inhibit ATPase activity more than either product alone. The results show that, in T. brucei, bisphosphonium compounds do not principally act on succinate dehydrogenase but on the mitochondrial FoF1 ATPase.

Citace poskytuje Crossref.org

000      
00000naa a2200000 a 4500
001      
bmc17000293
003      
CZ-PrNML
005      
20170118120635.0
007      
ta
008      
170103s2016 enk f 000 0|eng||
009      
AR
024    7_
$a 10.1016/j.ijpddr.2015.12.002 $2 doi
024    7_
$a 10.1016/j.ijpddr.2015.12.002 $2 doi
035    __
$a (PubMed)27054061
040    __
$a ABA008 $b cze $d ABA008 $e AACR2
041    0_
$a eng
044    __
$a enk
100    1_
$a Alkhaldi, Abdulsalam A M $u Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom. $7 gn_A_00004348
245    10
$a Trypanocidal action of bisphosphonium salts through a mitochondrial target in bloodstream form Trypanosoma brucei / $c AA. Alkhaldi, J. Martinek, B. Panicucci, C. Dardonville, A. Zíková, HP. de Koning,
520    9_
$a Lipophilic bisphosphonium salts are among the most promising antiprotozoal leads currently under investigation. As part of their preclinical evaluation we here report on their mode of action against African trypanosomes, the etiological agents of sleeping sickness. The bisphosphonium compounds CD38 and AHI-9 exhibited rapid inhibition of Trypanosoma brucei growth, apparently the result of cell cycle arrest that blocked the replication of mitochondrial DNA, contained in the kinetoplast, thereby preventing the initiation of S-phase. Incubation with either compound led to a rapid reduction in mitochondrial membrane potential, and ATP levels decreased by approximately 50% within 1 h. Between 4 and 8 h, cellular calcium levels increased, consistent with release from the depolarized mitochondria. Within the mitochondria, the Succinate Dehydrogenase complex (SDH) was investigated as a target for bisphosphonium salts, but while its subunit 1 (SDH1) was present at low levels in the bloodstream form trypanosomes, the assembled complex was hardly detectable. RNAi knockdown of the SDH1 subunit produced no growth phenotype, either in bloodstream or in the procyclic (insect) forms and we conclude that in trypanosomes SDH is not the target for bisphosphonium salts. Instead, the compounds inhibited ATP production in intact mitochondria, as well as the purified F1 ATPase, to a level that was similar to 1 mM azide. Co-incubation with azide and bisphosphonium compounds did not inhibit ATPase activity more than either product alone. The results show that, in T. brucei, bisphosphonium compounds do not principally act on succinate dehydrogenase but on the mitochondrial FoF1 ATPase.
650    _2
$a adenosintrifosfát $x metabolismus $7 D000255
650    _2
$a azidy $x farmakologie $7 D001386
650    _2
$a vápník $x metabolismus $7 D002118
650    _2
$a buněčné linie $7 D002460
650    _2
$a mitochondriální DNA $x metabolismus $7 D004272
650    _2
$a membránový potenciál mitochondrií $x účinky léků $7 D053078
650    _2
$a mitochondrie $x účinky léků $x genetika $x metabolismus $7 D008928
650    _2
$a organofosforové sloučeniny $x chemie $x farmakologie $7 D009943
650    _2
$a protonové ATPasy $x metabolismus $7 D006180
650    _2
$a RNA interference $7 D034622
650    _2
$a sukcinátdehydrogenasa $x metabolismus $7 D013385
650    _2
$a trypanocidální látky $x farmakologie $7 D014344
650    _2
$a Trypanosoma brucei brucei $x cytologie $x účinky léků $x růst a vývoj $7 D014346
650    _2
$a trypanozomóza africká $x parazitologie $7 D014353
655    _2
$a časopisecké články $7 D016428
655    _2
$a práce podpořená grantem $7 D013485
700    1_
$a Martinek, Jan $u Institute of Parasitology, Biology Centre & Faculty of Science, University of South Bohemia, České Budějovice, Czech Republic.
700    1_
$a Panicucci, Brian $u Institute of Parasitology, Biology Centre & Faculty of Science, University of South Bohemia, České Budějovice, Czech Republic.
700    1_
$a Dardonville, Christophe $u Instituto de Química Médica, IQM-CSIC, Juan de la Cierva 3, E-28006 Madrid, Spain.
700    1_
$a Zíková, Alena $u Institute of Parasitology, Biology Centre & Faculty of Science, University of South Bohemia, České Budějovice, Czech Republic.
700    1_
$a de Koning, Harry P $u Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
773    0_
$w MED00184051 $t International journal for parasitology. Drugs and drug resistance $x 2211-3207 $g Roč. 6, č. 1 (2016), s. 23-34
856    41
$u https://pubmed.ncbi.nlm.nih.gov/27054061 $y Pubmed
910    __
$a ABA008 $b sig $c sign $y a $z 0
990    __
$a 20170103 $b ABA008
991    __
$a 20170118120742 $b ABA008
999    __
$a ok $b bmc $g 1179433 $s 960860
BAS    __
$a 3
BAS    __
$a PreBMC
BMC    __
$a 2016 $b 6 $c 1 $d 23-34 $e 20151211 $i 2211-3207 $m International journal for parasitology. Drugs and drug resistance $n Int J Parasitol Drugs Drug Resist $x MED00184051
LZP    __
$a Pubmed-20170103

Najít záznam

Citační ukazatele

Možnosti archivace