Abstract
Because of the ever-increasing multidrug resistance in microorganisms, it is crucial that we find and develop new antibiotics, especially molecules with different targets and mechanisms of action than those of the antibiotics in use today. Translation is a fundamental process that uses a large portion of the cell’s energy, and the ribosome is already the target of more than half of the antibiotics in clinical use. However, this process is highly regulated, and its quality control machinery is actively studied as a possible target for new inhibitors. In bacteria, ribosomal stalling is a frequent event that jeopardizes bacterial wellness, and the most severe form occurs when ribosomes stall at the 3′-end of mRNA molecules devoid of a stop codon. Trans-translation is the principal and most sophisticated quality control mechanism for solving this problem, which would otherwise result in inefficient or even toxic protein synthesis. It is based on the complex made by tmRNA and SmpB, and because trans-translation is absent in eukaryotes, but necessary for bacterial fitness or survival, it is an exciting and realistic target for new antibiotics. Here, we describe the current and future prospects for developing what we hope will be a novel generation of trans-translation inhibitors.
Highlights
Protein synthesis, or translation, is a fundamental biological process that occurs on ribonucleoprotein nanomachines named ribosomes
Single-chain conformation, Transfer-Messenger RNA (tmRNA) exists as a two-piece molecule, a formation caused by a circular gene permutation that splits it into two molecules [40,41]
RNA-binding site, which later binds the messenger-like domain (MLD) to ensure that the resume codon is correctly recent cryo-electron microscopy structures of E. coli tmRNA–SmpB bound to a stalled ribosome [56,57], and the previous crystallographic study of trans-translation in Thermus thermophilus [58], both show that, just as in canonical translation, the presence of the protein in the decoding center induces reorientation of nucleotides A1492 and A1493 in helix 44
Summary
Translation, is a fundamental biological process that occurs on ribonucleoprotein nanomachines named ribosomes. It is generally accepted that among the most important bacteria to target, those in the ESKAPE pathogens group (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.) are of enormous interest when it comes to drug discovery [3,4]. They are the leading cause of nosocomial infections throughout the world, and most are multidrug-resistant isolates [5]. We discuss the potential of targeting this pathway with novel antimicrobial compounds
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