Ribosome‐targeting antibacterial agents: Advances, challenges, and opportunities

Abstract

Ribosomes, which synthesize proteins, are critical organelles for the survival and growth of bacteria. About 60% of approved antibiotics discovered so far combat pathogenic bacteria by targeting ribosomes. However, several issues, such as drug resistance and toxicity, have impeded the clinical use of ribosome‐targeting antibiotics. Moreover, the complexity of the bacteria ribosome structure has retarded the discovery of new ribosome‐targeting agents that are considered as the key to the drug‐resistance and toxicity. To deal with these challenges, efforts such as medicinal chemistry optimization, combination treatment, and new drug delivery system have been developed. But not enough, the development of structural biology and new screening methods bring powerful tools, such as cryo‐electron microscopy technology, advanced computer‐aided drug design, and cell‐free in vitro transcription/translation systems, for the discovery of novel ribosome‐targeting antibiotics. Thus, in this paper, we overview the research on different aspects of bacterial ribosomes, especially focus on discussing the challenges in the discovery of ribosome‐targeting antibacterial drugs and advances made to address issues such as drug‐resistance and selectivity, which, we believe, provide perspectives for the discovery of novel antibiotics.

The Time and Place for Nature in Drug Discovery

“…The preceding sections fall into the protein-centric world that dominates drug discovery; yet as new modalities emerge, the essence of many of such approaches is based on natural products. Targeting RNA in the Ribosome is an area where natural and semisynthetic drugs have a long pedigree, in particular in the antibiotic field. , The importance of sugar chemistry and glycomics in disease is receiving increasing attention, − and the inherent advantages of carbohydrates due to their solubility, specificity, and transporter recognition make this a field ripe for exploitation with natural methods, be it through molecular recognition of functionalized glycosides for activity or transporter recognition or a potential new world where the reading/writing/erasing of glycosyl functionality is exploited …”

“…Targeting RNA in the Ribosome 158 is an area where natural and semisynthetic drugs have a long pedigree, in particular in the antibiotic field. 159,160 The importance of sugar chemistry and glycomics in disease is receiving increasing attention, 161−163 and the inherent advantages of carbohydrates due to their solubility, specificity, and transporter recognition make this a field ripe for exploitation with natural methods, 164 be it through molecular recognition of functionalized glycosides for activity or transporter recognition or a potential new world where the reading/writing/erasing of glycosyl functionality is exploited. 165 Understanding and recognizing the common features of binding sites, transporters, and synthesizing enzymes should offer opportunities for defining motifs to pursue, be this validating a target with a natural product or using a natural fragment as the basis for further design.…”

Identification of Putative Drug Targets in Highly Resistant Gram-Negative Bacteria; and Drug Discovery Against Glycyl-tRNA Synthetase as a New Target

“…Considering the complex structure of bacterial ribosomes, targeting the pharmacophore of previous ribosomal antibiotics using ligand-based drug discovery might be a more appropriate alternative to receptor-based docking studies and molecular dynamics (MD). 44 …”

Biosynthesis and Engineered Overproduction of Everninomicins with Promising Activity against Multidrug-Resistant Bacteria

“…Ideally, antibiotics should be developed to act on targets different from the currently used drugs to prevent the cross-resistance. In this regard, ribosome-targeting orthosomycins represent a promising class of antibiotics against multidrug-resistant bacteria because they bind to a unique site of 50S subunit and therefore do not display cross-resistance to other types of antibiotics. − …”