title: Reduced in vitro doxycycline susceptibility in plasmodium falciparum field isolates from Kenya is associated with PfTetQ KYNNNN sequence polymorphism.
abstract: Doxycycline is widely used for malaria prophylaxis by international travelers. However, there is limited information on doxycycline efficacy in Kenya, and genetic polymorphisms associated with reduced efficacy are not well defined. In vitro doxycycline susceptibility profiles for 96 Plasmodium falciparum field isolates from Kenya were determined. Genetic polymorphisms were assessed in P. falciparum metabolite drug transporter (Pfmdt) and P. falciparum GTPase tetQ (PftetQ) genes. Copy number variation of the gene and the number of KYNNNN amino acid motif repeats within the protein encoded by PftetQ were determined. Reduced in vitro susceptibility to doxycycline was defined by 50% inhibitory concentrations (IC50s) of ≥35,000 nM. The odds ratio (OR) of having 2 PfTetQ KYNNNN amino acid repeats in isolates with IC50s of >35,000 nM relative to those with IC50s of <35,000 nM is 15 (95% confidence interval [CI], 3.0 to 74.3; P value of <0.0002). Isolates with 1 copy of the Pfmdt gene had a median IC50 of 6,971 nM, whereas those with a Pfmdt copy number of >1 had a median IC50 of 9,912 nM (P = 0.0245). Isolates with 1 copy of PftetQ had a median IC50 of 6,370 nM, whereas isolates with a PftetQ copy number of >1 had a median IC50 of 3,422 nM (P < 0.0007). Isolates with 2 PfTetQ KYNNNN motif repeats had a median IC50 of 26,165 nM, whereas isolates with 3 PfTetQ KYNNNN repeats had a median IC50 of 3,352 nM (P = 0.0023). PfTetQ sequence polymorphism is associated with a reduced doxycycline susceptibility phenotype in Kenyan isolates and is a potential marker for susceptibility testing.
authors: Department of Emerging Infectious Diseases-Global Emerging Infections Surveillance and Response System (DEID-GEIS) Program, United States Army Medical Research Unit-Kenya (USAMRU-K), Kenya Medical Research Institute (KEMRI)-Walter Reed Project, Kisumu, Kenya Department of Zoology, School of Biological and Physical Sciences, Maseno University, Maseno, Kenya.
authors: Angela O
authors: AO
authors: Achieng
authors: Department of Emerging Infectious Diseases-Global Emerging Infections Surveillance and Response System (DEID-GEIS) Program, United States Army Medical Research Unit-Kenya (USAMRU-K), Kenya Medical Research Institute (KEMRI)-Walter Reed Project, Kisumu, Kenya.
authors: Luiser A
authors: LA
authors: Ingasia
authors: Department of Emerging Infectious Diseases-Global Emerging Infections Surveillance and Response System (DEID-GEIS) Program, United States Army Medical Research Unit-Kenya (USAMRU-K), Kenya Medical Research Institute (KEMRI)-Walter Reed Project, Kisumu, Kenya.
authors: Dennis W
authors: DW
authors: Juma
authors: Department of Emerging Infectious Diseases-Global Emerging Infections Surveillance and Response System (DEID-GEIS) Program, United States Army Medical Research Unit-Kenya (USAMRU-K), Kenya Medical Research Institute (KEMRI)-Walter Reed Project, Kisumu, Kenya Department of Zoology, School of Biological and Physical Sciences, Maseno University, Maseno, Kenya.
authors: Agnes C
authors: AC
authors: Cheruiyot
authors: Department of Emerging Infectious Diseases-Global Emerging Infections Surveillance and Response System (DEID-GEIS) Program, United States Army Medical Research Unit-Kenya (USAMRU-K), Kenya Medical Research Institute (KEMRI)-Walter Reed Project, Kisumu, Kenya.
authors: Charles A
authors: CA
authors: Okudo
authors: Department of Emerging Infectious Diseases-Global Emerging Infections Surveillance and Response System (DEID-GEIS) Program, United States Army Medical Research Unit-Kenya (USAMRU-K), Kenya Medical Research Institute (KEMRI)-Walter Reed Project, Kisumu, Kenya.
authors: Redemptah A
authors: RA
authors: Yeda
authors: Department of Emerging Infectious Diseases-Global Emerging Infections Surveillance and Response System (DEID-GEIS) Program, United States Army Medical Research Unit-Kenya (USAMRU-K), Kenya Medical Research Institute (KEMRI)-Walter Reed Project, Kisumu, Kenya.
authors: Jelagat
authors: J
authors: Cheruiyot
authors: Department of Emerging Infectious Diseases-Global Emerging Infections Surveillance and Response System (DEID-GEIS) Program, United States Army Medical Research Unit-Kenya (USAMRU-K), Kenya Medical Research Institute (KEMRI)-Walter Reed Project, Kisumu, Kenya.
authors: Hoseah M
authors: HM
authors: Akala
authors: Department of Emerging Infectious Diseases-Global Emerging Infections Surveillance and Response System (DEID-GEIS) Program, United States Army Medical Research Unit-Kenya (USAMRU-K), Kenya Medical Research Institute (KEMRI)-Walter Reed Project, Kisumu, Kenya.
authors: Jacob
authors: J
authors: Johnson
authors: Department of Emerging Infectious Diseases-Global Emerging Infections Surveillance and Response System (DEID-GEIS) Program, United States Army Medical Research Unit-Kenya (USAMRU-K), Kenya Medical Research Institute (KEMRI)-Walter Reed Project, Kisumu, Kenya.
authors: Ben
authors: B
authors: Andangalu
authors: Department of Emerging Infectious Diseases-Global Emerging Infections Surveillance and Response System (DEID-GEIS) Program, United States Army Medical Research Unit-Kenya (USAMRU-K), Kenya Medical Research Institute (KEMRI)-Walter Reed Project, Kisumu, Kenya.
authors: Fredrick
authors: F
authors: Eyase
authors: Department of Zoology, School of Biological and Physical Sciences, Maseno University, Maseno, Kenya.
authors: Walter G Z O
authors: WG
authors: Jura
authors: Department of Emerging Infectious Diseases-Global Emerging Infections Surveillance and Response System (DEID-GEIS) Program, United States Army Medical Research Unit-Kenya (USAMRU-K), Kenya Medical Research Institute (KEMRI)-Walter Reed Project, Kisumu, Kenya edwin.kamau@us.army.mil.
authors: Edwin
authors: E
authors: Kamau
mesh_terms: D000962:Antimalarials / Q000494:pharmacology*; D056915:DNA Copy Number Variations; D004318:Doxycycline / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D007630:Kenya; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics*; D015800:Protozoan Proteins / Q000235:genetics
chemical_list: D000962:Antimalarials; D015800:Protozoan Proteins; D004318:Doxycycline