Doxycycline is traditionally used as a broad spectrum antibiotic, targeting bacterial ribosomes, but it is also commonly used as a prophylactic for malaria. There is substantial evidence to suggest that doxycycline targets the apicoplast in Plasmodium falciparum, and that it exhibits the characteristic “delayed death” phenotype of inhibitors of apicoplast translation.
Resistance to doxycycline in Plasmodium is not yet widespread, however pfmdt and pftetQ have been putatively identified as resistance markers in clinical isolates. An increased copy number of the two genes is associated with reduced doxycycline sensitivity, in addition to polymorphisms in pftetQ. PfMDT is a transporter that shares sequence similarity with bacterial doxycycline efflux transporters, which are involved in bacterial resistance to doxycycline. PfTetQ is sequentially similar to ribosomal protection proteins, which mediate doxycycline resistance in bacteria by outcompeting the drug for its binding pocket on the ribosome. We aim to validate the role of pfmdt and pftetQ in resistance to doxycycline in Plasmodium, and to begin functional characterisation of both proteins.