Antibiotics Targeting Translation Initiation in Prokaryotes

Approximately half of all known antibiotics target the translational apparatus [1–4], but because very few of them are specific inhibitors of the initiation phase of protein synthesis, translation initiation can be regarded as being a particularly underexploited antibiotic target. Furthermore, as initiation is the phase of protein synthesis displaying the greatest evolutionary divergence among all translation steps, the kingdom-specific characteristics of the initiation mechanisms render prokaryotic translation initiation a potentially unique and selective target of inhibitors directed against bacteria. This translation phase is also a potential antibiotic target within prokaryotic-type organelles (apicoplasts and mitochondria) present in protozoan parasites such as Plasmodium sp. and Toxoplasma sp. [5, 6]. These circumstances qualify translation initiation as an ideal target for the urgently needed new anti-infectives having novel modes of action and possibly novel chemical structures for which resistance mechanisms have not yet been developed in nature [1–3]. For a better reference to the subject of this chapter and for a better understanding of the mechanism of action of translation initiation inhibitors, we present subsequently a short description of translation initiation in bacteria. Furthermore, a mechanistic model compatible with all available experimental data of the events occurring immediately before and during formation of 30S initiation complex (IC) and 70S IC is schematically presented (Figure 17.1 and Figure 17.2). The specific steps targeted by the individual inhibitors are also indicated.