Breaking down the microbiology world one bite at a time
Roping in Resistant Microbial Outlaws
Howdy! Welcome to the wild west of bacterial infections, where antibiotic molecules and microbial outlaws are locked in a standoff at the molecular saloon. Saddle up and let me tell you a tale of a fearsome microscopic wrangler named lariocidin. This ain’t your average antimicrobial sheriff – it’s a lasso peptide.
Let’s back it up before we giddyup and go: peptides are chains of amino acids stitched together by the ribosome – the RNA-based macromolecular machine responsible for translating messenger RNA into protein. Among these, lasso peptides are biologically active compounds named for their unique knotted fold structures that form after ribosomal translation. As with all proteins, lasso peptides are initially assembled in a linear chain by the ribosome. Once completed, lasso peptides undergo post-translational modifications. Specialized enzymes cut off the initial amino acid sequence and tie the chain into a loop, linking the ends with an isopeptide bond, then thread the tail through the loop. This knot gives lasso peptides their legendary toughness, enabling them to act as natural antimicrobial agents.
Hold your horses, because lariocidin doesn’t ride alone! One of lariocidin’s isoforms, lariocidin-B (LAR-B), forms a rare and rugged double-lariat structure, like two lassos cinched tightly around one saddle horn. While the classic lasso peptide forms a single ring through an isopeptide bond, LAR-B ties a second isopeptide bond that locks down an additional segment of the peptide. This extra twist gives LAR-B even greater structural stability, making it more resistant to degradation and even tougher on bacterial varmints.
Until now, all lasso peptides that have been discovered have targeted various bacterial proteins or cell structures. In this study, researchers roped in a novel lasso peptide that turns its sights on its own maker: the ribosome. The ribosome is a prime target for antimicrobial agents because it is essential for life and offers plenty of pockets for chemically-diverse molecules to bind and stall protein synthesis. However, many bacteria have evolved to modify these binding sites – adding methyl groups or mutating the ribosomal RNA – to evade traditional antibiotics. Thankfully, lariocidin offers a new strategy: it binds to a previously-untapped site adjacent to the ribosome’s decoding center, where messenger RNA is matched with aminoacylated transfer RNAs to add a new amino acid to the growing chain. By blocking this unique site, lariocidin induces miscoding by causing the ribosome to misread the messenger RNA and produce faulty proteins.
Lariocidin didn’t just prove its grit in a test tube, but also went hoof-to-hoof with bacteria in living critters. In mouse models of bacterial infection, lariocidin significantly reduced bacterial load and helped to clear the infection without any signs of toxicity.
Now for the showdown. As antimicrobial resistance spreads faster than a prairie fire, new compounds like lariocidin and LAR-B are riding in to save the day. By targeting the ribosome in a unique fashion and packing structural features that enshrine stability, these lasso peptides offer a promising step forward in combating drug-resistant bacteria. Whether they end up in your medical arsenal or inspire future drug designs, the ribosome rustler and its double-lariat deputy have earned their place in the antibiotic hall of fame. Yee-haw!
Link to the original post: Jangra, M.; Travin, D.Y.; Aleksandrova, E.V.; Kaur, M.; Darwish, L.; Koteva, K.; Klepacki, D.; Wang, W.; Tiffany, M.; Sokaribo, A.; Coombes, B.L.; Vasquez-Lasop, N.; Polikanov, Y.S.; Mankin, A.S.; Wright, G.D. A broad-spectrum lasso peptide antibiotic targeting the bacterial ribosome. Nature 640, 1022-1030 (2025).
Featured image: Image generated using Google Gemini
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