Bacteriophages as anti-infective agents: recent developments and regulatory challenges.

The biennial meeting on 'Exploiting Bacteriophages for Bioscience, Biotechnology and Medicine', held in London, UK, on 20 January 2012, and chaired by George Salmond (University of Cambridge, UK) hosted over 50 participants representing 13 countries. The highly multidisciplinary meeting covered a diverse range of topics, reflecting the current expansion of interest in this field, including the use of bacteriophages as the source of biochemical reagents for molecular biology, bacteriophages for the treatment of human and animal diseases, bacteriophage-based diagnostics and therapeutic delivery technologies and necessity for, and regulatory challenges associated with, robust clinical trials of phage-based therapeutics. This report focuses on a number of presentations from the meeting relating to cutting-edge research on bacteriophages as anti-infective agents.

Anti-infective photodynamic biomaterials for the prevention of intraocular lens-associated infectious endophthalmitis

Bacterial attachment onto intraocular lenses (IOLs) during cataract extraction and IOL implantation is a prominent aetiological factor in the pathogenesis of infectious endophthalmitis. Photodynamic therapy (PDT) and photodynamic antimicrobial chemotherapy (PACT) have shown that photosensitizers are effective treatments for cancer, and in the photoinactivation of bacteria, viruses, fungi and parasites, in the presence of light. To date, no method of localizing the photocytotoxic effect of a photosensitizer at a biomaterial surface has been demonstrated. Here we show a method for concentrating this effect at a material surface to prevent bacterial colonization by attaching a porphyrin photosensitizer at, or near to, that surface, and demonstrate the principle using IOL biomaterials. Anionic hydrogel copolymers were shown to permanently bind a cationic porphyrin through electrostatic interactions as a thin surface layer. The mechanical and thermal properties of the materials showed that the porphyrin acts as a surface cross-linking agent, and renders surfaces more hydrophilic. Importantly, Staphylococcus epidermidis adherence was reduced by up to 99.0 ± 0.42% relative to the control in intense light conditions and 91.7± 5.99% in the dark. The ability to concentrate the photocytotoxic effect at a surface, together with a significant dark effect, provides a platform for a range of light-activated anti-infective biomaterial technologies.

IQ-motif peptides as novel anti-microbial agents

The IQ-motif is an amphipathic, often positively charged, a-helical, calmodulin binding sequence found in a number of eukaryote signalling, transport and cytoskeletal proteins. They share common biophysical characteristics with established, cationic a-helical antimicrobial peptides, such as the human cathelicidin LL-37. Therefore, we tested eight peptides encoding the sequences of IQ-motifs derived from the human cytoskeletal scaffolding proteins IQGAP2 and IQGAP3. Some of these peptides were able to inhibit the growth of Escherichia coli and Staphylococcus aureus with minimal inhibitory concentrations (MIC) comparable to LL-37. In addition some IQ-motifs had activity against the fungus Candida albicans. This antimicrobial activity is combined with low haemolytic activity (comparable to, or lower than, that of LL-37). Those IQ-motifs with anti-microbial activity tended to be able to bind to lipopolysaccharide. Some of these were also able to permeabilise the cell membranes of both Gram positive and Gram negative bacteria. These results demonstrate that IQ-motifs are viable lead sequences for the identification and optimisation of novel anti-microbial peptides. Thus, further investigation of the anti-microbial properties of this diverse group of sequences is merited.

Photosensitisers - the progression from photodynamic therapy to anti-infective surfaces

Introduction: The application of light as a stimulus in pharmaceutical systems and the associated ability to provide precise spatiotemporal control over location, wavelength and intensity, allowing ease of external control independent of environmental conditionals, has led to its increased use. Of particular note is the use of light with photosensitisers.

Areas covered: Photosensitisers are widely used in photodynamic therapy to cause a cidal effect towards cells on irradiation due to the generation of reactive oxygen species. These cidal effects have also been used to treat infectious diseases. The effects and benefits of photosensitisers in the treatment of such conditions are still being developed and further realised, with the design of novel delivery strategies. This review provides an overview of the realisation of the pharmaceutically relevant uses of photosensitisers, both in the context of current research and in terms of current clinical application, and looks to the future direction of research.

Expert opinion: Substantial advances have been and are being made in the use of photosensitisers. Of particular note are their antimicrobial applications, due to absence of resistance that is so frequently associated with conventional treatments. Their potency of action and the ability to immobilise to polymeric supports is opening a wide range of possibilities with great potential for use in healthcare infection prevention strategies.

Antimicrobial activity of neuropeptides against a range of micro-organisms from skin, oral, respiratory and gastrointestinal tract sites

Many neuropeptides are similar in size, amino acid composition and charge to antimicrobial peptides. This study aimed to determine whether the neuropeptides substance P (SP), neurokinin A (NKA), calcitonin gene-related peptide (CGRP), neuropeptide Y (NPY) and vasoactive intestinal polypeptide (VIP), displayed antimicrobial activity against Streptococcus mutans, Lactobacillus acidophilus, Enterococcus faecalis, Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa and Candida albicans. SP, NPY, VIP and CGRP displayed variable degrees of antimicrobial activity against all the pathogens tested with the exception of S. aureus. These antimicrobial activities add a further dimension to the immunomodulatory roles for neuropeptides in the inflammatory and immune responses. (c) 2008 Elsevier B.V. All rights reserved.

Endodontic 'Solutions'. Part 2:An audit comparing current practice in Belfast with UK and Republic of Ireland Dental Schools

Endodontic lubricants, irrigating solutions and medicaments help reduce the microbial load within root canals. Primary and secondary cases involve different microbes. Each'solution'or combinations thereof could play a significant role but no detailed guidelines exist on their use. An audit was undertaken to compare current practice in Belfast Dental School to the others across the UK and Republic of Ireland (ROI). This audit highlighted three main differences between Belfast and other dental schools. Many other institutions utilized other irrigants besides sodium hypochlorite (NaOCl), different intracanal medicaments, including calcium hydroxide, and higher concentrations of NaOCl. Having gathered this information, we ask, 'Is there sufficient evidence to change the endodontic regime currently used at Belfast Dental School?'. Using the findings from the literature review (Part 1), we introduce new evidence-based protocols for primary and secondary cases for use in Belfast Dental School. Clinical Relevance: In the absence of detailed clinical guidelines on the use of endodontic lubricants, irrigants and medicaments in primary and secondary cases, it is important to be aware of current practice in UK and ROI dental schools where dentists and specialists are trained.