Susceptibility of Plasmodium falciparum isolates to doxycycline is associated with pftetQ sequence polymorphisms and pftetQ and pfmdt copy numbers.
BACKGROUND
Doxycycline is used in combination with quinine for malaria treatment or alone for malaria chemoprophylaxis. However, the occurrence of malaria after doxycycline chemoprophylaxis has been reported. Identification of genetic determinants that contribute to the susceptibility of Plasmodium falciparum to doxycycline will be important for the detection and surveillance of doxycycline resistance.


METHODS
Sequence analysis of 11 genes (pftufA, pfEF-TS, pfmdt, pftetQ, pfrps3, pfrps7, pfrps8, pfrps9, pfrps11, pfrps14, and pfrps17) and evaluation of pfmdt and pftetQ copy numbers by quantitative real-time polymerase chain reaction were conducted in 90 African P. falciparum isolates that were obtained from 14 countries and that belonged to phenotypic groups differing in their doxycycline median inhibitory concentrations.


RESULTS
We found that pfmdt copy number of >1 (adjusted odds ratio [OR], 7.09 [95% confidence interval {CI}, 1.58-31.82]; P=.011), pftetQ copy number of >1 (adjusted OR, 5.23 [95% CI, 1.06-25.77]; P=.042), and KYNNNN amino acid motif repeats of <3 (adjusted OR, 3.00 [95% CI, 1.02-8.86]; P=.046) were independently associated with decreased susceptibility to doxycycline.


CONCLUSIONS
Our findings suggest that pfmdt and pftetQ copy numbers and pftetQ sequence polymorphisms are potential molecular markers of decreased in vitro susceptibility to doxycycline in African P. falciparum isolates.
Briolant
Sébastien
S
Unité de Recherche en Biologie et Epidémiologie Parasitaires, Institut de Recherche Biomédicale des Armées, Antenne de Marseille, Institut de Médecine Tropicale du Service de Santé des Armées, Allée du médecin colonel Eugène Jamot, France.
Wurtz
Nathalie
N
Zettor
Agnès
A
Rogier
Christophe
C
Pradines
Bruno
B
D001426:Bacterial Proteins / Q000235:genetics; D056915:DNA Copy Number Variations; D004318:Doxycycline / Q000378:metabolism*; D004351:Drug Resistance / Q000235:genetics*; D019450:Genes, MDR / Q000235:genetics; D006801:Humans; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
D001426:Bacterial Proteins; D004318:Doxycycline