"Lariocidin and ribosome-targeting lasso peptides as emerging antimicrobial agents against multidrug-resistant...

Lasso peptides are ribosomally synthesized and post-translationally modified peptides (RiPPs) with mechanically constrained structures that provide high stability and target selectivity. Among them, lariocidin (LAR), produced by Paenibacillus sp. M2, represents a recently discovered peptide antibiotic with a ribosome-targeting mechanism distinct from classical antibacterial agents. lariocidin binds a distinct site within the bacterial 30S ribosomal subunit, involving interactions with 16S rRNA and aminoacyl-tRNA, thereby disrupting protein synthesis through translocation inhibition and miscoding. This binding mode may help reduce cross-resistance with established ribosome-targeting antibiotics, including aminoglycosides and tetracyclines. Preclinical evidence indicates broad antibacterial activity, including activity against multidrug-resistant pathogens such as Acinetobacter baumannii, together with low spontaneous resistance, limited mammalian cytotoxicity, minimal hemolysis, and in vivo efficacy in mouse infection models. However, lariocidin remains at an early developmental stage, and key questions related to pharmacokinetics/pharmacodynamics, formulation, scalable production, resistance surveillance, and independent validation remain unresolved. This review critically examines LAR within the broader context of ribosome-targeting lasso peptides and evaluates their potential as microbial peptide antibiotic scaffolds for future antimicrobial discovery. Clinical Trial Registration. Not applicable. This manuscript is a review article and does not report a clinical trial. Lariocidin (LAR) is a ribosomally synthesized and post-translationally modified lasso peptide produced by Paenibacillus sp. M2. Its constrained topology supports binding to a distinct site on the bacterial 30S ribosomal subunit, where LAR contacts 16S rRNA helices h31, h32, and h34 and the A-site tRNA, thereby inhibiting translocation and inducing miscoding. LAR retained activity against the resistance determinants evaluated experimentally and showed activity against selected multidrug-resistant pathogens, including Acinetobacter baumannii, with efficacy in one murine infection model and no detected cytotoxicity or substantial haemolysis in the reported assays. Further development requires pharmacokinetic/pharmacodynamic characterization, formulation and manufacturing studies, repeat-dose toxicology, and independent preclinical validation. Abbreviations: LAR, lariocidin; MDR, multidrug resistant; PK/PD, pharmacokinetics/pharmacodynamics; RiPP, ribosomally synthesized and post-translationally modified peptide.