Lantibiotics: A Review of Their Structure, Mechanism and Biomedical Applications

Sumaiya Iram, Parthasarathi Kulkarni, Nagendra R, Venkatesh, Hanumanthachar Joshi,

doi:10.5281/zenodo.16632406

Review Paper | Open Access
Volume 03 | Issue 07 | Article Id IJPS/250307481

Lantibiotics: A Review of Their Structure, Mechanism and Biomedical Applications
Sumaiya Iram* Parthasarathi Kulkarni Nagendra R Venkatesh Hanumanthachar Joshi
Sarada Vilas College of Pharmacy, Mysuru, Karnataka, India

Abstract

Lantibiotics are a class of ribosomally synthesized and post-translationally modified peptides (RiPPs), known for their potent antimicrobial activity against Gram-positive bacteria, including multidrug-resistant strains. Characterized by unique amino acids such as lanthionine and methyllanthionine, Lantibiotics have garnered attention in food preservation, clinical medicine, and biotechnology. This review provides a detailed account of their classification, structural features, mechanisms of action, and representative compounds, along with their applications. Additionally, chemical structures are highlighted to provide visual insights into their innovative framework.

Keywords

Lantibiotics, Structure, Mechanism, Applications

Introduction

Lantibiotics (lanthionine-containing antibiotics) belong to a unique subset of bacteriocins. First recognized for their antimicrobial properties in the 1920s, they are now explored for their diverse bioactivities. They are synthesized ribosomally and undergo extensive post-translational modifications that contribute to their stability and efficacy.^[1]

The global rise of antibiotic resistance presents a profound threat to public health, necessitating the discovery and development of novel antimicrobial agents. Among the promising candidates to combat multidrug-resistant bacteria are lantibiotics—a unique class of ribosomally synthesized and post-translationally modified peptides (RiPPs) with potent antimicrobial activity, primarily against Gram-positive bacteria. Derived from the term lanthionine-containing antibiotics, Lantibiotics are characterized by the presence of unusual amino acids, such as lanthionine and methyllanthionine, which result from intramolecular thioether bridges. These modifications not only contribute to the structural stability of lantibiotics but also enhance their interaction with bacterial targets, making them highly effective at low concentrations.

Lantibiotics are typically produced by Gram-positive bacteria, especially members of the genus Lactococcus, Streptococcus, and Bacillus, as part of their competitive survival strategy. The most well-known Lantibiotic Nisin has been extensively studied and widely used as a food preservative for over 60 years, demonstrating the safety and practical applicability of this compound class. Nisin’s mechanism of action includes binding to lipid II, a crucial precursor in bacterial cell wall biosynthesis, thereby inhibiting peptidoglycan formation and simultaneously forming membrane pores. This dual mode of action significantly reduces the likelihood of resistance development compared to traditional antibiotics.

The biosynthesis of Lantibiotics involves a well-orchestrated enzymatic process. A precursor peptide, consisting of a leader and core region, is first synthesized by the ribosome. The leader peptide guides the core to modification enzymes that install the characteristic thioether rings via dehydration of serine and threonine residues followed by Michael addition of Cysteine thiols. The mature peptide is then exported out of the cell, where proteases remove the leader sequence to yield the active Lantibiotic. This biosynthetic pathway is encoded by gene clusters that often include immunity genes, ensuring the producing organism’s protection from its own antibiotic.

Recent advances in genome mining, synthetic biology and analytical techniques have accelerated the discovery of novel Lantibiotics and enabled the rational engineering of known variants for improved properties. Bioinformatics tools can now identify Lantibiotics biosynthetic gene clusters across bacterial genomes, facilitating the identification of cryptic or uncharacterized Lantibiotics producers. Additionally, heterologous expression systems and site-directed mutagenesis have made it feasible to generate and evaluate Lantibiotics analogs with enhanced antimicrobial spectra, stability, or reduced toxicity.

Despite their promise, the clinical development of lantibiotics faces several challenges, including poor solubility, potential immunogenicity, and high production costs. Nonetheless, their potent activity against resistant pathogens such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococci (VRE), and Clostridium difficile underscores their therapeutic potential. Furthermore, the modular nature of lantibiotic biosynthetic pathways offers a versatile platform for engineering next-generation antimicrobials.^[2]

2. Classification of Lantibiotics ^{[3] [4]}

Lantibiotics are classified into four main types:

Class I: Modified by separate enzymes LanB (dehydration) and LanC (cyclization):

Nisin – Produced by Lactococcus lactis; used as a food preservative (E234).
Subtilin – Produced by Bacillus subtilis; similar to Nisin.
Lacticin 481 – From Lactococcus lactis; has a different ring structure.

Class II: Modified by a bifunctional enzyme LanM (dehydration and cyclization):

Lichenicidin – Produced by Bacillus licheniformis.
Haloduracin – Produced by Bacillus halodurans.
Mutacin 1140 – Produced by Streptococcus mutans.

Class III: Large Lantibiotics with enzymatic lytic activity but reduced antimicrobial potency:

Cerecidin – Produced by Bacillus cereus.
Microbisporicin – Broad-spectrum, with activity against MRSA.

Class IV: Rare, with unique modifications and less characterized structures. These are still under investigation and include peptides with atypical post-translational modifications beyond lanthionine rings.

3. Structural Characteristics

Key structural features include:

Presence of lanthionine (Lan) and methyllanthionine (MeLan).
Dehydrated residues like dehydroalanine (Dha) and dehydrobutyrine (Dhb).
Multiple intramolecular thioether bridges that create polycyclic ring systems.
Resistance to heat and proteolytic enzymes.

Structural Representation

4. Mechanism of Action

Lantibiotics primarily act via:

Binding to lipid II, an essential precursor in bacterial cell wall synthesis.
Forming pores in the bacterial membrane, leading to ion leakage and cell death.
Inhibiting peptidoglycan polymerization and trans glycosylation.

5. Representative Lantibiotics and Their Applications

Lantibiotics	Producer Organism	Mechanism & Features	Applications
Nisin	Lactococcus lactis	Lipid II binding, pore formation. Stable and active in low pH.	Food preservation, anti-biofilm, topical antimicrobials.^[5][6][7]
Lacticin 3147	Lactococcus lactis	Two-component Lantibiotics. One binds lipid II, the other forms pores.	Dairy product preservation, effective against C. difficile.^[8][9][10]
Gallidermin	Staphylococcus gallinarum	Lipid II binding, no pore formation.	Potential anti-MRSA, coating for medical implants^.[11]
Epidermin	Staphylococcus epidermidis	Similar to gallidermin, N-terminal lipid II binding motif.	Skin probiotic potential.^[12]
Mutacin 1140	Streptococcus mutans	Potent lipid II binding.	Dental applications, oral cavity antiseptic.^[13]
Actagardine	Actinoplanes garbadinensis	Type-B lantibiotic, lipid II target.	Investigated as an antibacterial drug scaffold.[^14]
Subtilin	Bacillus subtilis	Pore formation, structurally similar to Nisin.	Used in food as biopreservative.^[15]
Duramycin	Streptoverticillium cinnamoneus	Binds phosphatidylethanolamine.	Anti-inflammatory, antiviral, molecular imaging.^[16]

6. Applications

Food Preservation: Nisin and subtilin are widely used as natural food preservatives, particularly in dairy and meat products due to their effectiveness and GRAS (Generally Recognized as Safe) status.^[17]

Clinical Use: Gallidermin and lacticin 3147 are under investigation for treating resistant bacterial infections. Nisin has shown potential in managing mastitis and as an adjuvant in cancer therapy.^[18]

Oral and Topical Applications: Mutacin 1140 has been explored for preventing dental caries, while epidermin may contribute to maintaining healthy skin micro biota.^[19]

Molecular Imaging and Anti-Inflammatory Agents: Duramycin is used for imaging applications, especially in detecting phosphatidylethanolamine exposure during apoptosis.^[20]

7. Advantages of Lantibiotics Over Conventional Antibiotics

Lantibiotics offer several advantages over conventional antibiotics, making them promising alternatives in both clinical and industrial settings. Unlike traditional antibiotics that often target general bacterial processes like protein or DNA synthesis, lantibiotics exert their antimicrobial effect by binding specifically to lipid II, a crucial precursor in bacterial cell wall synthesis. This unique mode of action reduces the likelihood of resistance development, which is a major limitation of many conventional antibiotics. Furthermore, lantibiotics typically exhibit narrow-spectrum activity, mainly against Gram-positive bacteria, which helps preserve the host’s normal microbiota and reduce the risk of secondary infections such as antibiotic-associated diarrhea. They are also generally more biocompatible and less toxic, with some, like Nisin, recognized as safe (GRAS) and widely used as natural preservatives in food products. Moreover, lantibiotics are biodegradable, posing minimal environmental risk compared to conventional antibiotics, which can persist and promote resistance in ecosystems. These collective benefits highlight the potential of lantibiotics as safer, more targeted and sustainable alternatives to traditional antibiotics.^[21][22]

Benefits of Lantibiotics^[23][24][25]

Advantage	Explanation
1. Potent Antimicrobial Activity	Highly effective against Gram-positive bacteria like MRSA, VRE, C. difficile.
2. Unique Mechanism of Action	Bind to lipid II (cell wall precursor), making it hard for bacteria to develop resistance.
3. Low Resistance Development	Unlike traditional antibiotics, resistance to lantibiotics is rare and slow.
4. Safe and Biocompatible	Many (e.g., nisin) are non-toxic and GRAS-approved for food and pharmaceutical use.
5. Dual Mode of Action	Some lantibiotics both inhibit cell wall synthesis and form membrane pores, increasing lethality.
6. Stable and Heat-Resistant	Maintain activity over a range of pH and temperature, useful in food and pharmaceutical formulations.
7. Can Be Bioengineered	Their peptide nature allows for genetic modification to improve spectrum and potency.
8. Use in Food Preservation	Natural preservatives like nisin extend shelf life without harmful chemicals.
9. Environmentally Friendly	Biodegradable and do not contribute to environmental antibiotic pollution.
10. Applications Beyond Medicine	Useful in agriculture, veterinary use, and cosmetic formulations as antimicrobials.

CONCLUSION

Lantibiotics offer a promising alternative to traditional antibiotics, particularly in combating Gram-positive pathogens. Their unique structures and mechanisms open up possibilities for both therapeutic and industrial applications. Future research should focus on improving production yields, expanding the antimicrobial spectrum, and understanding resistance mechanisms. Lantibiotics are a unique class of peptide antibiotics characterized by the presence of unusual amino acids like lanthionine. They are produced by Gram-positive bacteria and exhibit strong antimicrobial activity, particularly against other Gram-positive organisms, including drug-resistant strains. Their mode of action often involves pore formation in bacterial membranes or inhibition of cell wall synthesis. Due to their potent activity, specificity, and relatively low resistance development, Lantibiotics are promising candidates for therapeutic applications. However, challenges such as stability, delivery, and production costs remain. Continued research and development may unlock their full potential in clinical and pharmaceutical settings.

REFERENCES

Alkhatib Z, Abts A, Mavaro A, Schmitt L and Smits SH. Lantibiotics: how do producers become self-protected? J Biotechnol. 2012 Jun 15; 159(3):145-54.
Ongey EL, Neubauer P. Lanbiotics: biosynthesis, structure, mechanisms of action, biosynthetic gene clusters regulation, and engineering. Appl Microbiol Biotechnol. 2016; 100 (22):9661–9681.
World Health Organization (WHO). 2021 AWaRe Classification Database of Antibiotics. Geneva: WHO; 2021 Available from: https://www.who.int/publications/i/item/2021-aware-classification
Centers for Disease Control and Prevention (CDC). Antibiotic Use. Atlanta: CDC; 2023 Available from: https://www.cdc.gov/antibiotic-use/index.html
Kuraji R, Kaneko T, Wakimoto T, Suzuki H. Lantibiotics from oral streptococci and their antimicrobial activity against biofilms. NPJ Biofilms Microbiomes. 2024; 10(1):3.
Madera C, Gálvez A, Martínez-Bueno M, Valdivia E. New insights into lantibiotic mechanisms through omics approaches. Front Microbiol. 2024; 15:1443.
El-Kazzaz SS, Matar GM, Rizk DEE. Lantibiotics: a novel therapeutic option for multidrug-resistant bacteria. J Glob Antimicrob Resist. 2020;22:263–269.
Field D, Cotter PD, Ross RP, Hill C. The dawning of a ‘golden era’ in lantibiotic bioengineering. Appl Environ Microbiol. 2007;73(21):6845–6851.
Piper C, Draper LA, Cotter PD, Ross RP, Hill C. A comparison of the activities of the lantibiotics nisin and lacticin 3147 against drug-resistant clinical pathogens. J Antimicrob Chemother. 2009;64(3):546–551.
Rea MC, Sit CS, Clayton E, O'Connor PM, Whittal RM, Zheng J, et al. Thuricin CD, a posttranslationally modified bacteriocin with a narrow spectrum of activity against Clostridium difficile. J Antimicrob Chemother. 2007; 59(5):745–751.
Pérez-Ramos A, Miguelez EM, Romero-Gil V, Ruiz-Larrea F, Requena T, Bartolomé B. In vitro activity of bacteriocinogenic lactic acid bacteria against foodborne pathogens. Antibiotics (Basel). 2021; 10(11):1354.
Bremen K, Lages S, Omansen TF, Nørregaard-Madsen M, Abou Hachem M, Meyer RL. Identification of novel lantibiotics by genome mining of environmental Bacillus strains. Front Microbiol. 2024;15:1225.
Hillman JD, Novak J, Sagura E, Gutierrez JA, Brooks TA, Crowley PJ. Genetic and functional analysis of the lantibiotic Smb in Streptococcus mutans. Appl Environ Microbiol. 1998; 64(1):324–328.
Chatterjee C, Paul M, Xie L, van der Donk WA. Biosynthesis and mode of action of lantibiotics. Chem Rev. 2005; 105(2):633–684.
Banerjee S, Hansen JN. Structure and expression of a gene encoding the precursor of nisin, a small protein antibiotic. J Biol Chem. 1988; 263(20):9508–9514.
Zhao L, van der Donk WA, Goodman SD, McCormick BA, Haldar J. Nisin-biogel: a new approach to combat biofilms of Clostridium difficile and other pathogens. Mol Pharm. 2013; 10(11):4263–4271.
Gharsallaoui A, Oulahal N, Joly C, Degraeve P. Nisin as a Food Preservative: Part 1: Physicochemical Properties, Antimicrobial Activity, and Main Uses. Crit Rev Food Sci Nutr. 2016 Jun 10; 56(8):1262-74.
Nguyen T, Brody H, Lin GH, Rangé H, Kuraji R, Ye C, Kamarajan P, Radaic A, Gao L, Kapila Y. Probiotics, including nisin-based probiotics, improve clinical and microbial outcomes relevant to oral and systemic diseases. Periodontol 2000. 2020 Feb;82(1):173-185.
Kuraji R, Ye C, Zhao C, Gao L, Martinez A, Miyashita Y, Radaic A, Kamarajan P, Le C, Zhan L, Range H, Sunohara M, Numabe Y, Kapila YL. Nisin lantibiotic prevents NAFLD liver steatosis and mitochondrial oxidative stress following periodontal disease by abrogating oral, gut and liver dysbiosis. NPJ Biofilms Microbiomes. 2024 Jan 17; 10(1):3.
Steiner I, Errhalt P, Kubesch K, Hubner M, Holy M, Bauer M, Müller M, Hinterberger S, Widmann R, Mascher D, Freissmuth M, Kneussl M. Pulmonary pharmacokinetics and safety of nebulized duramycin in healthy male volunteers. Naunyn Schmiedebergs Arch Pharmacol. 2008 Sep;378(3):323-33.
Cotter PD, Ross RP, Hill C. Bacteriocins—a viable alternative to antibiotics? Nat Rev Microbiol. 2013;11(2):95–105.
Field D, Cotter PD, Hill C, Ross RP. The dawning of a ‘golden era’ in lantibiotic bioengineering. Curr Opin Biotechnol. 2015;31:1–6.
Dischinger J, Basi Chipalu SB, Bierbaum G. Lantibiotics: promising candidates for future applications in health care. Int J Med Microbiol. 2014;304(1):51–62.
Van Heel AJ, de Jong A, Montalbán-López M, Kok J, Kuipers OP. BAGEL3: automated identification of genes encoding bacteriocins and (non-) bactericidal posttranslationally modified peptides. Nucleic Acids Res. 2013;41.
Sahl HG, Bierbaum G. Lantibiotics: biosynthesis and biological activities of uniquely modified peptides from Gram-positive bacteria. Annu Rev Microbiol. 1998;52:41–79.