Using the Bacterial Ribosome as a Discovery Platform for Peptide-Based Antibiotics

Abstract

The threat of bacteria resistant to multiple antibiotics poses a major public health problem requiring immediate and coordinated action worldwide. While infectious pathogens have become increasingly resistant to commercially available drugs, antibiotic discovery programs in major pharmaceutical companies have produced no new antibiotic scaffolds in 40 years. As a result, new strategies must be sought to obtain a steady supply of novel scaffolds capable of countering the spread of resistance. The bacterial ribosome is a major target for antimicrobials and is inhibited by more than half of the antibiotics used today. Recent studies showing that the ribosome is a target for several classes of ribosomally synthesized antimicrobial peptides point to ribosome-targeting peptides as a promising source of antibiotic scaffolds. In this Perspective, we revisit the current paradigm of antibiotic discovery by proposing that the bacterial ribosome can be used both as a target and as a tool for the production and selection of peptide-based antimicrobials. Turning the ribosome into a high-throughput platform for the directed evolution of peptide-based antibiotics could be achieved in different ways. One possibility would be to use a combination of state-of-the-art microfluidics and genetic reprogramming techniques, which we will review briefly. If it is successful, this strategy has the potential to produce new classes of antibiotics for treating multi-drug-resistant pathogens.

The Multifaceted Roles of Proline in Cell Behavior

“…The control of L-Pro metabolism in human cells is relatively poorly understood, even though it might have a great impact on human health (Figure 10). For instance, PrAMPs displaying potent antimicrobial activity and low toxicity for human cells could be efficient tools to fight multidrug-resistant pathogens, a serious public health concern (Charon et al, 2019). Salivary proline-rich peptides able to neutralize microbe attacks could contribute to avoiding the development of dental caries, an infectious disease that affects billions of people (Werneck et al, 2010;Stromberg et al, 2017).…”

Exploring patterns of cytonuclear incompatibility in Pelargonium section Ciconium

“…Plant ribosomal structural models are becoming available, but so far mainly for the model organism S. oleraceae (Bieri et al 2017, Perez-Boerema et al 2018. Doing this would help us gain insight into practical topics such as protein synthesis (Levy et al 2020) and antibiotic resistance (Davies 2010, Charon et al 2019, but also into the fundamental evolutionary questions on life as we know it (Bowman et al 2020, Moelling andBroecker 2021).…”

“…Another important field where insights in ribosomal evolution are valuable is the study of antibiotic resistance. More than half of antibiotic in use today inhibit the bacterial ribosome (Charon et al 2019) and these compounds act by directly upsetting physico-chemical interactions in the ribosome inhibiting aa translation to functional peptides. Antibiotic resistance often arises from structural ribosomal changes that evolved as an adaptational response to neutralize and counteract the disrupting effects of antibiotics (Davies et al 2010, Charon et al 2019.…”

Directed Evolution in Drops: Molecular Aspects and Applications

“…As their use is becoming common to treat acute infections, chronic diseases, and even some types of cancer, droplet microfluidics can help one to discover peptides with novel properties. Droplet-based strategies could be adopted to identify antimicrobial peptides, 100 discover novel antiviral peptides to treat respiratory diseases, 101 or find anticancer peptides. 102 Research in self-replicating nucleic acids is another field that is gaining importance.…”