Targeting Protein Translation in Organelles of the Apicomplexa. Issue 12 (December 2016) - Goodman, Christopher D.
Abstract : Antibiotics inhibiting protein translation have long been used to treat and prevent infections by apicomplexan parasites. These compounds kill parasites by inhibiting organellar translation, and most act specifically against the apicoplast, a relict plastid in apicomplexans. Drug resistance in Plasmodium and other apicomplexans dictates a need for development of novel targets. Some apicoplast inhibitors have a delayed onset of action, so they cannot replace fast-acting drugs, although they still fulfil important roles in treating and preventing infections. The plethora of bacterial-like actors in the translation machinery of parasite mitochondria and plastids presents validated targets with strong potential for selectivity. Here we discuss existing drugs that inhibit organellar translation, and explore targets that may be further exploited in antiparasitic drug design. Trends: Recent molecular and chemical rescue studies confirm that the apicoplast is the primary target for several antiparasitic drugs targeting organellar protein synthesis. Many new compounds inhibiting organellar protein synthesis in apicomplexans have recently been developed, but few appear to be superior to antibiotics in current use. Nonetheless, several additional compounds may be suitable as replacements if resistance to existing antibiotics becomes a major problem. Antiparasitic compounds that inhibit organellar ribosomes are numerous and are widely studied. tRNA synthetases are emerging as a second category of targets for diverse and potent chemical classes with activity against multiple parasite life stages. Selectivity and safety issues remain to be addressed for the most active of these.