An overview of lantibiotic biosynthetic machinery promiscuity and its impact on antimicrobial discovery

ABSTRACT

Introduction: The continued emergence of drug resistant bacteria within the nosocomial and community environment recalcitrant to conventional antimicrobial therapies has enforced the requirement for novel therapeutics. This has led to a renewed interest in peptide antimicrobials, including ribosomally synthesized peptides termed lantibiotics. Lantibiotics represent a novel class of agents that many studies have highlighted as effective against a range of pathogenic bacteria.

Areas covered: In this review, the modular nature of lantibiotic synthesis is discussed and how this can be exploited not only to improve known lantibiotics but also for the creation of new to nature lantibiotics exhibiting improved pharmacological properties, antimicrobial activity and ability to bypass bacterial resistance mechanisms.

Expert opinion: The use of combinatorial biosynthetic systems to combine different modules or ring structures of known lantibiotics have also been utilized to create new to nature lantibiotics. To fully exploit the available information and its application to lantibiotic engineering, additional structure activity relationship (SAR) analysis is required to fully understand the impact of certain post-translational modifications and the impact they have upon the activity, stability and pharmacological properties.

KEYWORDS:

• Bioengineering
• lantibiotics
• infectious disease
• genome mining
• anti-infectives

Article highlights

• Lantibiotics are ribosomally synthesised antimicrobial peptides that undergo extensive post-translational modification (PTM)

• Knowledge of how these PTMs function can be applied to bioengineer lantibiotics with improved pharmacological properties.

• The promiscuous nature of lantibiotic biosynthetic genes can be exploited in the engineering process to develop therapeutic peptides, however the capabilities of these enzymes are not limited to lantibiotics.

• Combinatorial biosynthesis has led to the discovery of multiple new to nature lantibiotics with increased antimicrobial activity and ability to bypass common lantibiotic resistance mechanisms.

• The ability to develop efficient lantibiotic expression systems to screen the extensive number of novel lantibiotic genes identified from whole genome sequencing will undoubtedly increase the number of lantibiotics in pre-clinical and clinical trials.

This box summarizes key points contained in the article.

Declaration of interest

SK Sandiford is an employee of Evotec (UK). She has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript was not funded.