The intestinal barrier, consisting of the vascular endothelium, epithelial cell lining, and mucus layer, covers a surface of about 400 m2. The integrity of the gut wall is sustained by transcellular proteins forming tight junctions between the epithelial cells. Protected by three layers of mucin, the gut wall forms a non-permeable barrier, keeping digestive enzymes and microorganisms within the luminal space, separate from the blood stream. Microorganisms colonizing the gut may produce bacteriocins in an attempt to outcompete pathogens. Production of bacteriocins in a harsh and complex environment such as the gastro-intestinal tract (GIT) may be below minimal inhibitory concentration (MIC) levels. At such low levels, the stability of bacteriocins may be compromised. Despite this, most bacteria in the gut have the ability to produce bacteriocins, distributed throughout the GIT. With most antimicrobial studies being performed in vitro, we know little about the migration of bacteriocins across epithelial barriers. The behavior of bacteriocins in the GIT is studied ex vivo, using models, flow cells, or membranes resembling the gut wall. Furthermore, little is known about the effect bacteriocins have on the immune system. It is generally believed that the peptides will be destroyed by macrophages once they cross the gut wall. Studies done on the survival of neurotherapeutic peptides and their crossing of the brain–blood barrier, along with other studies on small peptides intravenously injected, may provide some answers. In this review, the stability of bacteriocins in the GIT, their effect on gut epithelial cells, and their ability to cross epithelial cells are discussed. These are important questions to address in the light of recent papers advocating the use of bacteriocins as possible alternatives to, or used in combination with, antibiotics.

Lanthipeptides are ribosomally synthesized and post translationally 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 represents a group of bioactive peptides that holds 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 towards the therapeutic applications and production of lanthipeptides, specifically looking at heterologous expression systems.

c Staphylococcus aureus is a bacterial pathogen responsible for the majority of skin and soft tissue infections. Antibiotics are losing their efficacy as treatment for skin and soft tissue infections as a result of increased resistance in a variety of pathogens, including S. aureus. It is thus imperative to explore alternative antimicrobial treatments to ensure future treatment options for skin and soft tissue infections. A select few lantibiotics, a group of natural defense peptides produced by bacteria, inhibit the growth of numerous clinical S. aureus isolates, including methicillin-resistant strains. In this study, the antimicrobial activities of nisin, clausin, and amyloliquecidin, separately administered, were compared to that of a mupirocin-based ointment, which is commonly used as treatment for S. aureus-induced skin infections. Full-thickness excisional wounds, generated on the dorsal surfaces of mice, were infected with a bioluminescent strain of S. aureus (strain Xen 36). The infections were monitored in real time using in vivo bioluminescent imaging. Lantibiotic treatments significantly reduced the bioluminescence of S. aureus Xen 36 to a level similar to that recorded with mupirocin treatment. Wound closure, however, was more pronounced during lantibiotic treatment. Lantibiotics thus have the potential to be used as an alternative treatment option for S. aureus-induced skin infections.

With the effectiveness of therapeutic agents ever decreasing and the increased incidence of multi-drug resistant pathogens, there is a clear need for administration of more potent, potentially more toxic, drugs. Alternatively, biopharmaceuticals may hold potential but require specialized protection from premature in vivo degradation. Thus, a paralleled need for specialized drug delivery systems has arisen. Although cell-mediated drug delivery is not a completely novel concept, the few applications described to date are not yet ready for in vivo application, for various reasons such as drug-induced carrier cell death, limited control over the site and timing of drug release and/or drug degradation by the host immune system. Here, we present our hypothesis for a new drug delivery system, which aims to negate these limitations. We propose transport of nanoparticle-encapsulated drugs inside autologous macrophages polarized to M1 phenotype for high mobility and treated to induce transient phagosome maturation arrest. In addition, we propose a significant shift of existing paradigms in the study of host-microbe interactions, in order to study microbial host immune evasion and dissemination patterns for their therapeutic utilization in the context of drug delivery. We describe a system in which microbial strategies may be adopted to facilitate absolute control over drug delivery, and without sacrificing the host carrier cells. We provide a comprehensive summary of the lessons we can learn from microbes in the context of drug delivery and discuss their feasibility for in vivo therapeutic application. We then describe our proposed “synthetic microbe drug delivery system” in detail. In our opinion, this multidisciplinary approach may hold the solution to effective, controlled drug delivery.

Aims:  To determine if nisin F‐loaded self‐setting brushite cement could control the growth of Staphylococcus aureus in vivo. Methods and Results:  Brushite cement was prepared by mixing equimolar concentrations of β‐tricalcium phosphate and monocalcium phosphate monohydrate. Nisin F was added at 5·0, 2·5 and 1·0% (w/w) and the cement moulded into cylinders. In vitro antibacterial activity was determined using a delayed agar diffusion assay. Release of nisin F from the cement was determined using BCA protein assays. Based on scanning electron microscopy and X‐ray diffraction analysis, nisin F did not cause significant changes in cement structure or chemistry. Cement containing 5·0% (w/w) nisin F yielded the most promising in vitro results. Nisin F‐loaded cement was implanted into a subcutaneous pocket on the back of mice and then infected with S. aureus Xen 36. Infection was monitored for 7 days, using an in vivo imaging system. Nisin F prevented S. aureus infection for 7 days and no viable cells were isolated from the implants. Conclusions:  Nisin F‐loaded brushite cement successfully prevented in vivo growth of S. aureus. Significance and Impact of the Study:  Nisin F incorporated into bone cement may be used to control S. aureus infection in vivo.