Resistance to apicoplast translational inhibitors in Plasmodium

The spread of drug-resistant Plasmodium threatens malaria control efforts. Thus, understanding the mechanisms of resistance is crucial for implementing effective treatments and prevention strategies. The prokaryote-like translational machinery encoded by the apicoplast is the apparent target of several antibiotics with antimalarial activity. Among them, doxycycline and clindamycin are widely used for malaria treatment and/or chemoprophylaxis. However, the mechanisms underlying Plasmodium resistance to apicoplast-targeting antibiotics, and the evolution of such resistance mechanisms, remain largely unknown. In this review, we summarise reported cases of resistance to apicoplast translational inhibitors uncovered in either laboratory or clinical settings. We highlight the potential evolutionary pathway of doxycycline resistance, explore why resistance to these antibiotics remains rare in the field, and assess whether expanding their use in malaria treatment and prevention is a viable strategy.