Lasso Peptide Antibiotics: A New Hope against Bacteria

Today we take a break from the usual DNA nanotech and AI-protein stuff to explore a new weapon in our fight again multi-drug resistant bacteria: a novel class of peptide antibiotics! Will this do the trick? Read to find out!

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Taming Bacteria with Lasso Peptides

The Growing Threat of Antibiotic Resistance

You know what I am scared of? Multi-drug resistant bacteria (MDR bacteria). And I am not alone: the World Health Organization has deemed antimicrobial resistance (AMR) a critical threat. In 2019 alone, it contributed to over 4.5 million deaths.

Bacteria, and other microorganisms, naturally evolve resistance to antimicrobial drugs through genetic changes. Unfortunately, misuse and overuse of antimicrobials has accelerated this process. As a result, infections become harder to treat, treatments fail, and medical procedures become riskier.

The situation for bacteria is particularly bleak (or good, if you are a bacteria): according to WHO statistics, for urinary tract infections cased by E.coli, 1 in 5 is resistant to standard antibiotics! These are not the weak E.coli we use in the lab, I guess.

Gram-negative bacteria like E.coli are concerning: they have highly impermeable membranes and often present multidrug resistant genes. At the same time, conventional antibiotic discovery pipelines are drying up, especially for molecules with broad spectrum activity and novel mechanisms of action, which would make it harder for the bacteria to develop resistance.

Lasso Peptides: Robust Molecular Knots

Here is where today’s paper comes in. The team discovered a new type of lasso peptides with strong antibacterial activity, a new mechanism of action and broad spectrum activity. But first: what are lasso peptides?

Lasso peptides are short chains of amino acids characterized by a unique, knotted three-dimensional structure. Most peptides are produced by specific enzymes, but lasso peptides are special. They are ribosomally produced and then post-translationally modified to create a looped structure. This lasso topology confers an exceptional stability and resistance to degradation, and several lasso peptides exhibit antimicrobial activity!

In this new paper, the team collected different bacterial strains from the environment and grew them in the lab for one whole year! Why so long? It allows even overlooked, slow growing bacteria to be found. The researchers then tested the extracts from these bacteria for their antibacterial effect: and magic happened! The extracts from a strain of Paenibacillus had a strong antibacterial effect. As an aside, while researching for this I found out that Paenibacillus creates some amazingly beautiful colonies! But back to the paper.

LAR: Lariocidin to Fight Bacteria

The team isolated the new lasso peptide and they baptized it lariocidin, LAR for friends. They actually discovered 3 variants:

• LAR: the most abundant, with powerful antibacterial effect.

• LAR B: the second most abundant, a double lasso with powerful activity.

• LAR C: Too scarce to characterize, but still interesting.

LAR showed a powerful bactericidal activity, but how does it work? The scientists wondered.

A Functional Double Whammy: Inhibition of Protein Synthesis and Miscoding

Turns out, LAR interacts with the bacterial ribosome, where it interferes with protein production. In particular, lariocidin binds to the small ribosomal subunit, in a site previously unexploited by drugs. The ribosome is an important target for antibiotics, but most drugs binds a few common sites. Unfortunately, bacteria are becoming resistant to antibiotics acting on these “overused” sites. This is why the discovery of a class of antibiotics targeting a new site is so exciting!

LAR interacts with the ribosomes in 2 ways, and this creates a double attack on protein synthesis in bacteria:

1. Inhibition of Ribosomal Translocation

   A reminder from molecular biology class. During protein synthesis, the ribosome must translocate along the mRNA so that the tRNA shifts in different sites: from A to P to E.

   Lariocidin binds strongly to the phosphate backbone of the ribosome (don’t forget, a ribosome is made of proteins and RNA!). This binding happens at just the right position to stop the translocation from happening, by blocking the necessary movements in the different subunits. In this way, the ribosome gets stuck and can’t produce proteins!

2. Induction of Mistranslation

   in addition, LAR also makes a strong contact with a loop region in the tRNA, when a protein is being produced. This interaction appear to lower the fidelity of protein synthesis, leading to non-functional proteins.

Towards Real-World Applications: Testing in Animal Models

This is all well and good, but the team was not satisfied. Of course it’s amazing to find a new antibiotic, but does it actually work?

Well, they first tested LAR’s safety: the compound is specific for bacteria, and does not harm mammalian cells! After this, they moved into mice models: and it worked brilliantly. They infected mice with bacteria resistant to common drugs: 100% of the treated animals survived, while sadly all the control mice died. This is great news for the possible clinical development of LAR as a treatment of serious bacterial infections.

To summarize, lariocidin is a new class of antibacterial agents, with a unique mechanism of action: binding to a new site in the ribosome. This makes it less vulnerable to resistance, and with its effectiveness and selectivity, LAR can be a great starting scaffold to design much needed new antibiotics! So go and read the whole paper here!

And as always, thank you for reading! What do you think, did we find the antibiotics of tomorrow? Are you also worried? Do you see a possible path to commercialization? Reply and let me know!

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