Therapeutic Application of Lantibiotics and Other Lanthipeptides: Old and New Findings

Abstract

Lanthipeptides are ribosomally synthesized and posttranslationally modified peptides, with modifications that are incorporated during biosynthesis by dedicated enzymes. Various modifications of the peptides are possible, resulting in a highly diverse group of bioactive peptides that offer a potential reservoir for use in the fight against a plethora of diseases. Their activities range from the antimicrobial properties of lantibiotics, especially against antibiotic-resistant strains, to antiviral activity, immunomodulatory properties, antiallodynic effects, and the potential to alleviate cystic fibrosis symptoms. Lanthipeptide biosynthetic genes are widespread within bacterial genomes, providing a substantial repository for novel bioactive peptides. Using genome mining tools, novel bioactive lanthipeptides can be identified, and coupled with rapid screening and heterologous expression technologies, the lanthipeptide drug discovery pipeline can be significantly sped up. Lanthipeptides represent a group of bioactive peptides that hold great potential as biotherapeutics, especially at a time when novel and more effective therapies are required. With this review, we provide insight into the latest developments made toward the therapeutic applications and production of lanthipeptides, specifically looking at heterologous expression systems.

Keywords: antimicrobial agents; antimicrobial peptides; antiviral agents; drug resistance; heterologous expression systems; lanthipeptides; lantibiotics.

FIG 1

Biosynthesis and classification of lanthipeptides. (A) Generalized scheme of lanthipeptide biosynthesis (precursor peptide made up of leader and core peptides). (B and C) Four main classes of synthetases (B) and additional modification enzymes (C) involved in PTM of lanthipeptides. (D) Sequence similarity network of lanthipeptide core peptides generated with the Enzyme Function Initiative-Enzyme Similarity Tool (EST-EFI [https://efi.igb.illinois.edu/efi-est/]) (E value cutoff, 10⁻³) and visualized in Cytoscape (v.3.8.0). Abbreviations: LanN, lysinoalanine synthase; LanD, flavin-containing Cys decarboxylase; LanJ_A/B, dehydrogenase (A indicates Zn²⁺ dependent and B indicates flavin dependent); LanO, oxidoreductase; PaeN, acetylation (paenibacillin); CinX, α-ketoglutarate (α-KG)/iron(II)-dependent hydroxylase (cinnamycin); GarO, flavin-dependent monooxygenase (actagardine); MibO, hydroxylase (microbisporicin); MibH, Trp halogenase (microbisporicin); and Zn-BM, zinc binding motif.

FIG 2

Lanthipeptide antimicrobial and antiviral modes of action. (A) Antimicrobial mode of action of lipid II binding lantibiotics. The peptidoglycan precursor lipid II (1) is the binding site for lipid II binding lantibiotics, which bind to the pyrophosphate cage of lipid II (2). Once bound, the lantibiotics can undergo a conformational change, resulting in insertion into the membrane and subsequent pore formation (3). Additionally, binding of lantibiotics to lipid II can result in inhibition of cell wall biosynthesis (4). (B) Proposed antiviral mechanism of lanthipeptides. Envelope viruses harbor lipids in their virus envelope derived from the host cell membranes, including phosphatidylethanolamine (PE) (1). Lanthipeptides effective against envelope virus bind to PE distributed on the outer virus envelope (2), which can interfere with viral entry into host cells (3) and virolysis (4). The figure was created with BioRender.