Kenyan Plasmodium falciparum field isolates: correlation between pyrimethamine and chlorcycloguanil activity in vitro and point mutations in the dihydrofolate reductase domain

Sixty-nine Kenyan Plasmodium falciparum field isolates were tested in vitro against pyrimethamine (PM), chlorcycloguanil (CCG), sulfadoxine (SD), and dapsone (DDS), and their dihydrofolate reductase (DHFR) genotypes were determined. The in vitro data show that CCG is more potent than PM and that DDS...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Antimicrobial agents and chemotherapy Jg. 42; H. 1; S. 164
Hauptverfasser: Nzila-Mounda, A, Mberu, E K, Sibley, C H, Plowe, C V, Winstanley, P A, Watkins, W M
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 01.01.1998
Schlagworte:
Animals
Antimalarials - pharmacology
Humans
Kenya
Malaria, Falciparum - drug therapy
Plasmodium falciparum - drug effects
Plasmodium falciparum - enzymology
Point Mutation
Proguanil - analogs & derivatives
Proguanil - pharmacology
Protozoan Proteins - drug effects
Protozoan Proteins - genetics
Pyrimethamine - pharmacology
Sensitivity and Specificity
Tetrahydrofolate Dehydrogenase - drug effects
Tetrahydrofolate Dehydrogenase - genetics
Triazines
Kenya
ISSN:0066-4804
Online-Zugang:Weitere Angaben
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
Abstract Sixty-nine Kenyan Plasmodium falciparum field isolates were tested in vitro against pyrimethamine (PM), chlorcycloguanil (CCG), sulfadoxine (SD), and dapsone (DDS), and their dihydrofolate reductase (DHFR) genotypes were determined. The in vitro data show that CCG is more potent than PM and that DDS is more potent than SD. DHFR genotype is correlated with PM and CCG drug response. Isolates can be classified into three distinct groups based on their 50% inhibitory concentrations (IC50s) for PM and CCG (P < 0.01) and their DHFR genotypes. The first group consists of wild-type isolates with mean PM and CCG IC50s of 3.71 +/- 6.94 and 0.24 +/- 0.21 nM, respectively. The second group includes parasites which all have mutations at codon 108 alone or also at codons 51 or 59 and represents one homogeneous group for which 25- and 6-fold increases in PM and CCG IC50s, respectively, are observed. Parasites with mutations at codons 108, 51, and 59 (triple mutants) form a third distinct group for which nine- and eightfold increases in IC50s, respectively, of PM and CCG compared to the second group are observed. Surprisingly, there is a significant decrease (P < 0.01) of SD and DDS susceptibility in these triple mutants. Our data show that more than 92% of Kenyan field isolates have undergone at least one point mutation associated with a decrease in PM activity. These findings are of great concern because they may indicate imminent PM-SD failure, and there is no affordable antimalarial drug to replace PM-SD (Fansidar).
AbstractList Sixty-nine Kenyan Plasmodium falciparum field isolates were tested in vitro against pyrimethamine (PM), chlorcycloguanil (CCG), sulfadoxine (SD), and dapsone (DDS), and their dihydrofolate reductase (DHFR) genotypes were determined. The in vitro data show that CCG is more potent than PM and that DDS is more potent than SD. DHFR genotype is correlated with PM and CCG drug response. Isolates can be classified into three distinct groups based on their 50% inhibitory concentrations (IC50s) for PM and CCG (P < 0.01) and their DHFR genotypes. The first group consists of wild-type isolates with mean PM and CCG IC50s of 3.71 +/- 6.94 and 0.24 +/- 0.21 nM, respectively. The second group includes parasites which all have mutations at codon 108 alone or also at codons 51 or 59 and represents one homogeneous group for which 25- and 6-fold increases in PM and CCG IC50s, respectively, are observed. Parasites with mutations at codons 108, 51, and 59 (triple mutants) form a third distinct group for which nine- and eightfold increases in IC50s, respectively, of PM and CCG compared to the second group are observed. Surprisingly, there is a significant decrease (P < 0.01) of SD and DDS susceptibility in these triple mutants. Our data show that more than 92% of Kenyan field isolates have undergone at least one point mutation associated with a decrease in PM activity. These findings are of great concern because they may indicate imminent PM-SD failure, and there is no affordable antimalarial drug to replace PM-SD (Fansidar).Sixty-nine Kenyan Plasmodium falciparum field isolates were tested in vitro against pyrimethamine (PM), chlorcycloguanil (CCG), sulfadoxine (SD), and dapsone (DDS), and their dihydrofolate reductase (DHFR) genotypes were determined. The in vitro data show that CCG is more potent than PM and that DDS is more potent than SD. DHFR genotype is correlated with PM and CCG drug response. Isolates can be classified into three distinct groups based on their 50% inhibitory concentrations (IC50s) for PM and CCG (P < 0.01) and their DHFR genotypes. The first group consists of wild-type isolates with mean PM and CCG IC50s of 3.71 +/- 6.94 and 0.24 +/- 0.21 nM, respectively. The second group includes parasites which all have mutations at codon 108 alone or also at codons 51 or 59 and represents one homogeneous group for which 25- and 6-fold increases in PM and CCG IC50s, respectively, are observed. Parasites with mutations at codons 108, 51, and 59 (triple mutants) form a third distinct group for which nine- and eightfold increases in IC50s, respectively, of PM and CCG compared to the second group are observed. Surprisingly, there is a significant decrease (P < 0.01) of SD and DDS susceptibility in these triple mutants. Our data show that more than 92% of Kenyan field isolates have undergone at least one point mutation associated with a decrease in PM activity. These findings are of great concern because they may indicate imminent PM-SD failure, and there is no affordable antimalarial drug to replace PM-SD (Fansidar).
Sixty-nine Kenyan Plasmodium falciparum field isolates were tested in vitro against pyrimethamine (PM), chlorcycloguanil (CCG), sulfadoxine (SD), and dapsone (DDS), and their dihydrofolate reductase (DHFR) genotypes were determined. The in vitro data show that CCG is more potent than PM and that DDS is more potent than SD. DHFR genotype is correlated with PM and CCG drug response. Isolates can be classified into three distinct groups based on their 50% inhibitory concentrations (IC50s) for PM and CCG (P < 0.01) and their DHFR genotypes. The first group consists of wild-type isolates with mean PM and CCG IC50s of 3.71 +/- 6.94 and 0.24 +/- 0.21 nM, respectively. The second group includes parasites which all have mutations at codon 108 alone or also at codons 51 or 59 and represents one homogeneous group for which 25- and 6-fold increases in PM and CCG IC50s, respectively, are observed. Parasites with mutations at codons 108, 51, and 59 (triple mutants) form a third distinct group for which nine- and eightfold increases in IC50s, respectively, of PM and CCG compared to the second group are observed. Surprisingly, there is a significant decrease (P < 0.01) of SD and DDS susceptibility in these triple mutants. Our data show that more than 92% of Kenyan field isolates have undergone at least one point mutation associated with a decrease in PM activity. These findings are of great concern because they may indicate imminent PM-SD failure, and there is no affordable antimalarial drug to replace PM-SD (Fansidar).
Author Mberu, E K
Sibley, C H
Watkins, W M
Nzila-Mounda, A
Plowe, C V
Winstanley, P A
Author_xml – sequence: 1
  givenname: A
  surname: Nzila-Mounda
  fullname: Nzila-Mounda, A
  email: wellcome@users.africaonline.co.ke
  organization: Wellcome Trust Research Laboratories, Kenya Medical Research Institute, Nairobi. wellcome@users.africaonline.co.ke
– sequence: 2
  givenname: E K
  surname: Mberu
  fullname: Mberu, E K
– sequence: 3
  givenname: C H
  surname: Sibley
  fullname: Sibley, C H
– sequence: 4
  givenname: C V
  surname: Plowe
  fullname: Plowe, C V
– sequence: 5
  givenname: P A
  surname: Winstanley
  fullname: Winstanley, P A
– sequence: 6
  givenname: W M
  surname: Watkins
  fullname: Watkins, W M
BackLink https://www.ncbi.nlm.nih.gov/pubmed/9449279$$D View this record in MEDLINE/PubMed
BookMark eNotkD1PAzEMhjMUAQU2VqRMbC33kcs1bKjiSyDBAHPlc1walEuOJAe6X8Vf5Fo6-bX96LX1TtnEeUeMnefZPM-LxRUAzkUxz-e5FBN2nGVSzsQiE0dsGuNnNvaVyg7ZoRJCFbU6Zr9P5AZw_NVCbL02fcvXYNF0ELbSkNXcRG8hUbzm6EOgURvveEPph8jxbgimpbSB1jji4DTHjfUBB7T-owdnLAdM5tukgRvHxxr8Duu8cYm3fdr5xe0ybYhrsxl08OvdTR5I95ggjnPfgnGn7GD8L9LZvp6w97vbt-XD7Pnl_nF58zwDoeo0E4i1KgGgyfJ13pQVqApwoesKgRYga1XLrKyxREmNLipRYCFGmBByIYGKE3b579sF_9VTTKvWRCRrwZHv46pWUpZKiRG82IN905JedWMaEIbVPuHiD4aEg-I
CitedBy_id crossref_primary_10_1186_1475_2875_11_275
crossref_primary_10_1086_587845
crossref_primary_10_1016_S1368_7646_98_80007_1
crossref_primary_10_1111_j_1365_3156_2004_01239_x
crossref_primary_10_1186_1471_2156_11_57
crossref_primary_10_1146_annurev_micro_012220_064343
crossref_primary_10_1046_j_1365_3156_2002_00974_x
crossref_primary_10_1371_journal_pone_0019636
crossref_primary_10_1016_j_actatropica_2009_07_008
crossref_primary_10_1128_AAC_44_4_991_996_2000
crossref_primary_10_1016_S1471_4922_01_02085_2
crossref_primary_10_1016_S1995_7645_13_60001_2
crossref_primary_10_1016_j_trstmh_2004_07_002
crossref_primary_10_1002_cmdc_200600240
crossref_primary_10_1016_S0035_9203_03_90163_5
crossref_primary_10_1016_S0399_077X_00_88264_5
crossref_primary_10_1016_j_parint_2009_04_004
crossref_primary_10_1186_s40249_020_00712_4
crossref_primary_10_1016_j_actatropica_2006_01_005
crossref_primary_10_1016_j_molbiopara_2004_09_005
crossref_primary_10_1016_j_medmal_2006_05_005
crossref_primary_10_1128_AAC_48_9_3598_3601_2004
crossref_primary_10_1016_S0035_9203_01_90207_X
crossref_primary_10_1073_pnas_182295999
crossref_primary_10_1186_1475_2875_2_17
crossref_primary_10_1007_s12041_011_0072_z
crossref_primary_10_1016_j_pt_2007_03_002
crossref_primary_10_1186_s12936_020_03454_8
crossref_primary_10_1186_1475_2875_9_247
crossref_primary_10_1016_S0140_6736_02_11198_6
crossref_primary_10_1186_1475_2875_8_34
crossref_primary_10_1124_pr_57_1_4
crossref_primary_10_1186_1475_2875_10_283
crossref_primary_10_1016_j_meegid_2017_05_013
crossref_primary_10_1016_j_pt_2005_12_011
crossref_primary_10_1016_j_actatropica_2007_04_008
crossref_primary_10_1016_j_parint_2022_102653
crossref_primary_10_1017_S0031182013000954
crossref_primary_10_1002_cbdv_201000111
crossref_primary_10_1016_j_actatropica_2012_10_013
crossref_primary_10_1016_j_ijpara_2010_08_008
crossref_primary_10_1046_j_1472_8206_2003_00164_x
crossref_primary_10_1016_j_actatropica_2005_04_002
crossref_primary_10_1016_j_jgar_2021_03_003
crossref_primary_10_1128_JCM_01683_06
crossref_primary_10_1186_1475_2875_9_338
crossref_primary_10_1016_S0169_4758_99_01622_1
crossref_primary_10_1016_S1286_4579_01_01525_8
crossref_primary_10_1086_588198
crossref_primary_10_1074_jbc_274_53_37781
crossref_primary_10_1016_S0169_4758_99_01419_2
crossref_primary_10_1186_s12936_022_04385_2
crossref_primary_10_1016_S1286_4579_01_01523_4
crossref_primary_10_1016_S0035_9203_02_90108_2
crossref_primary_10_1016_j_trstmh_2008_01_018
crossref_primary_10_1016_S0001_706X_02_00264_4
crossref_primary_10_1016_S1471_4922_01_02185_7
crossref_primary_10_1186_1475_2875_9_190
crossref_primary_10_1080_00365540310016862
crossref_primary_10_1186_1475_2875_13_250
crossref_primary_10_1021_jm030165t
crossref_primary_10_1128_AAC_42_7_1811
crossref_primary_10_1016_S0014_4894_02_00108_X
crossref_primary_10_1016_S0169_4758_99_01420_9
crossref_primary_10_1016_S0166_6851_02_00240_2
crossref_primary_10_1016_j_parint_2016_10_024
crossref_primary_10_1016_j_actatropica_2016_09_008
crossref_primary_10_4103_ijmr_IJMR_1688_15
crossref_primary_10_1016_S0166_6851_01_00207_9
crossref_primary_10_1128_AAC_45_1_187_195_2001
ContentType Journal Article
DBID CGR
CUY
CVF
ECM
EIF
NPM
7X8
DOI 10.1128/aac.42.1.164
DatabaseName Medline
MEDLINE
MEDLINE (Ovid)
MEDLINE
MEDLINE
PubMed
MEDLINE - Academic
DatabaseTitle MEDLINE
Medline Complete
MEDLINE with Full Text
PubMed
MEDLINE (Ovid)
MEDLINE - Academic
DatabaseTitleList MEDLINE - Academic
MEDLINE
Database_xml – sequence: 1
  dbid: NPM
  name: PubMed
  url: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed
  sourceTypes: Index Database
– sequence: 2
  dbid: 7X8
  name: MEDLINE - Academic
  url: https://search.proquest.com/medline
  sourceTypes: Aggregation Database
DeliveryMethod no_fulltext_linktorsrc
Discipline Medicine
Biology
Pharmacy, Therapeutics, & Pharmacology
ExternalDocumentID 9449279
Genre Research Support, Non-U.S. Gov't
Journal Article
GeographicLocations Kenya
GeographicLocations_xml – name: Kenya
GrantInformation_xml – fundername: Wellcome Trust
GroupedDBID ---
.55
.GJ
0R~
23M
2WC
39C
3O-
4.4
53G
5GY
5RE
5VS
6J9
AAGFI
ACGFO
ADBBV
AENEX
AGNAY
AGVNZ
AI.
ALMA_UNASSIGNED_HOLDINGS
AOIJS
BAWUL
BTFSW
C1A
CGR
CS3
CUY
CVF
DIK
E3Z
EBS
ECM
EIF
EJD
F5P
FRP
GX1
H13
HH5
HYE
HZ~
H~9
J5H
K-O
KQ8
L7B
LSO
MVM
NEJ
NPM
O9-
OK1
P2P
RHI
RNS
RPM
RSF
TR2
UHB
VH1
W2D
W8F
WH7
WHG
WOQ
X7M
X7N
XOL
Y6R
ZGI
ZXP
~A~
7X8
ID FETCH-LOGICAL-a497t-4cc793aaab01f1b35a95ac8d75cae8a67976037c3c6ebd2542c24ab0eca146ae2
IEDL.DBID 7X8
ISICitedReferencesCount 93
ISICitedReferencesURI http://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=Summon&SrcAuth=ProQuest&DestLinkType=CitingArticles&DestApp=WOS_CPL&KeyUT=000071301100027&url=https%3A%2F%2Fcvtisr.summon.serialssolutions.com%2F%23%21%2Fsearch%3Fho%3Df%26include.ft.matches%3Dt%26l%3Dnull%26q%3D
ISSN 0066-4804
IngestDate Thu Sep 04 15:51:54 EDT 2025
Mon Jul 21 05:51:54 EDT 2025
IsDoiOpenAccess false
IsOpenAccess true
IsPeerReviewed true
IsScholarly true
Issue 1
Language English
LinkModel DirectLink
MergedId FETCHMERGED-LOGICAL-a497t-4cc793aaab01f1b35a95ac8d75cae8a67976037c3c6ebd2542c24ab0eca146ae2
Notes ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
OpenAccessLink https://aac.asm.org/content/aac/42/1/164.full.pdf
PMID 9449279
PQID 79663994
PQPubID 23479
ParticipantIDs proquest_miscellaneous_79663994
pubmed_primary_9449279
PublicationCentury 1900
PublicationDate 1998-Jan
19980101
PublicationDateYYYYMMDD 1998-01-01
PublicationDate_xml – month: 01
  year: 1998
  text: 1998-Jan
PublicationDecade 1990
PublicationPlace United States
PublicationPlace_xml – name: United States
PublicationTitle Antimicrobial agents and chemotherapy
PublicationTitleAlternate Antimicrob Agents Chemother
PublicationYear 1998
SSID ssj0006590
Score 1.8767757
Snippet Sixty-nine Kenyan Plasmodium falciparum field isolates were tested in vitro against pyrimethamine (PM), chlorcycloguanil (CCG), sulfadoxine (SD), and dapsone...
SourceID proquest
pubmed
SourceType Aggregation Database
Index Database
StartPage 164
SubjectTerms Animals
Antimalarials - pharmacology
Humans
Kenya
Malaria, Falciparum - drug therapy
Plasmodium falciparum - drug effects
Plasmodium falciparum - enzymology
Point Mutation
Proguanil - analogs & derivatives
Proguanil - pharmacology
Protozoan Proteins - drug effects
Protozoan Proteins - genetics
Pyrimethamine - pharmacology
Sensitivity and Specificity
Tetrahydrofolate Dehydrogenase - drug effects
Tetrahydrofolate Dehydrogenase - genetics
Triazines
Title Kenyan Plasmodium falciparum field isolates: correlation between pyrimethamine and chlorcycloguanil activity in vitro and point mutations in the dihydrofolate reductase domain
URI https://www.ncbi.nlm.nih.gov/pubmed/9449279
https://www.proquest.com/docview/79663994
Volume 42
WOSCitedRecordID wos000071301100027&url=https%3A%2F%2Fcvtisr.summon.serialssolutions.com%2F%23%21%2Fsearch%3Fho%3Df%26include.ft.matches%3Dt%26l%3Dnull%26q%3D
hasFullText
inHoldings 1
isFullTextHit
isPrint
link http://cvtisr.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwpV1La9wwEBZp05Ze-tgmJH3OoeQUb_yQLasUyhIaemgWH9Kyt2Us2axhLW9tb8C_qn-xIz_YU-mhF9tgGQlmPPNpNDMfYx-lxIBzTtaPnAltUETkoJcKR6dBnueudtO-ldLP72K5jFcrmRyxz1MtjE2rnGxib6h1pWyM_EoQLidnyr_sfjmWM8qerY4EGg_YcUBAxuq0WB16hUfhEGEhp-rw2OVT2rsfXy0W13Puz725ZzsN_A1a9i7m5vn_Le4FezZCS1gMuvCSHWVmxh4PZJPdjD25HY_RZ-wiGRpWd5dwd6i_ai7hApJDK-vuFftNdrhDAwlh7LLSxb6EHLc2Dbu2jzb7DQrSXgtYP4GyTB9Dbh2M-V-w6yx_QLvBkmYGNBrUZlvVqlM2aISm2IItrbAMFlAYoHtd9cN2VWFaKPdDqkBjXxJWBV1sOk2-o58Tatt4tiVHDLoqsTAn7MfN17vrb85I8eAgl6J1uFJkIBAxdb3cS4MQZYgq1iJUmMUYCUJLbiBUoKIs1bSZ9ZXPaXCmkEw8Zv4pe2gqk50x0JHOA9Sx76WKeyoiQxRqiSlXQRjl2j1nHybZrekXsuciaLJq36wn6Z2z00H8693Q6WMtOZe-kK__-ekb9nQoVrSxmbfsmGTRZO_YI3XfFk39vldMui6T2z8eVvSy
linkProvider ProQuest
openUrl ctx_ver=Z39.88-2004&ctx_enc=info%3Aofi%2Fenc%3AUTF-8&rfr_id=info%3Asid%2Fsummon.serialssolutions.com&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Kenyan+Plasmodium+falciparum+field+isolates%3A+correlation+between+pyrimethamine+and+chlorcycloguanil+activity+in+vitro+and+point+mutations+in+the+dihydrofolate+reductase+domain&rft.jtitle=Antimicrobial+agents+and+chemotherapy&rft.au=Nzila-Mounda%2C+A&rft.au=Mberu%2C+E+K&rft.au=Sibley%2C+C+H&rft.au=Plowe%2C+C+V&rft.date=1998-01-01&rft.issn=0066-4804&rft.volume=42&rft.issue=1&rft.spage=164&rft_id=info:doi/10.1128%2FAAC.42.1.164&rft.externalDBID=NO_FULL_TEXT
thumbnail_l http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/lc.gif&issn=0066-4804&client=summon
thumbnail_m http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/mc.gif&issn=0066-4804&client=summon
thumbnail_s http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/sc.gif&issn=0066-4804&client=summon