The use of antibiotics has revolutionized medicine, greatly improving our capacity to save
millions of lives from otherwise deadly bacterial infections. Unfortunately, the health-associated benefits
provided by antibiotics have been counteracted by bacteria developing or acquiring resistance
mechanisms. The negative impact to public health is now considered of high risk due to the rapid
spreading of multi-resistant strains. More than 60 % of clinically relevant antibiotics of natural origin
target the ribosome, the supramolecular enzyme which translates the genetic information into proteins.
Although many of these antibiotics bind the small ribosomal subunit, only a few are reported to inhibit
the initiation of protein synthesis, with none reaching commercial availability. Counterintuitively, translation
initiation is the most divergent phase of protein synthesis between prokaryotes and eukaryotes, a
fact which is a solid premise for the successful identification of drugs with reduced probability of undesired
effects to the host. Such a paradox is one of its kind and deserves special attention. In this review,
we explore the inhibitors that bind the 30S ribosomal subunit focusing on both the compounds with
proved effects on the translation initiation step and the underreported translation initiation inhibitors. In
addition, we explore recent screening tests and approaches to discover new drugs targeting translation.
Keywords: Antibiotics, Ribosome, 30S ribosomal subunit, Protein synthesis, Translation initiation, Screening tests, Drug
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