Current developments in lantibiotic discovery for treating Clostridium difficile infection

ABSTRACT

Introduction: Clostridium difficile is a major cause of healthcare-associated diarrhea linked to the misuse of antimicrobials and the corresponding deleterious impact they have on the protective microbiota of the gut. Resistance to agents used to treat C. difficile including metronizadole and vancomycin has been reported highlighting the need for novel agents. Lantibiotics represent a novel class of agents that many studies have highlighted as effective against C. difficile.

Areas covered: In this review lantibiotics including nisin, actagardine, mersacidin, NAI-107 and MU-1140 that exhibit good activity against C.difficile, all of which are currently in the preclinical phase of investigation are discussed. The lantibiotic NVB302, which has completed phase I clinical trials for the treatment of C. difficile, is also described.

Expert opinion: Lantibiotics represent promising candidates for the treatment of C. difficile infections due to their novel mode of action, which is thought to decrease the potential of resistance developing and the fact they often possess a less deleterious effect on the protective gut microbiota when compared to traditional agents. They are also extremely amenable to bioengineering approaches and the incorporation of synthetic biology to produce more potent variants.

KEYWORDS:

• Lantibiotic
• bioengineering
• infection
• Clostridium

Article highlights

• The level of CDIs and their recurrence within the clinical environment combined with development of resistance to traditional treatment warrants the investigation of novel agents.

• Lantibiotics are ribosomally synthesized antimicrobial peptides that exhibit potent activity against a range of bacteria, including C. difficile.

• Lantibiotics possess novel modes of action and therefore lower rates of resistance development and in the treatment of C. difficile has a less deleterious effect on the protective gut microbiota thus leading to lower recurrence rates of infection.

• Bioengineering and semi-synthesis strategies can be applied to lantibiotic structures to improve multiple properties including potency, stability, and spectrum of activity.

• Synergism between conventional antimicrobials and lantibiotics can be used to potentiate their activity and reduce toxicity.

• The success of agents including NVB302 and MU-1140 in preclinical and clinical trials highlights the potential of synthetic biology and bioengineering in optimizing the properties of lantibiotics, tailoring them to specific applications.

This box summarizes key points contained in the article.

Declaration of interest

SK Sandiford is an employee of Evotec (UK) Ltd. The authors have 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.