Mytilusl defensin

Defensins are a family of cationic antimicrobial peptides active against a broad range of infectious microbes including bacteria, viruses and fungi, playing important roles as innate effectors and immune modulators in immunological control of microbial infection. Their antibacterial properties and unique mechanisms of action have garnered considerable interest in developing defensins into a novel class of natural antibiotic peptides to fend off pathogenic infection by bacteria, particularly those resistant to conventional antibiotics. However, serious pharmacological and technical obstacles, some of which are unique to defensins and others are common to peptide drugs in general, have hindered the development and clinical translation of defensins as anti-infective therapeutics. To overcome them, several technologies have been developed, aiming for improved functionality, prolonged circulation time, enhanced proteolytic stability and bioavailability, and efficient and controlled delivery and release of defensins to the site of infection. Additional challenges include the alleviation of potential toxicity of defensins and their cost-effective manufacturing. In this review, we briefly introduce defensin biology, focus on various transforming strategies and practical techniques developed for defensins and their derivatives as antibacterial therapeutics, and conclude with a summation of future challenges and possible solutions.

Defensins are an effector component of the innate immune system with broad antimicrobial activity. Humans express two types of defensins, α- and β-defensins, which have antiviral activity against both enveloped and non-enveloped viruses. The diversity of defensin-sensitive viral species reflects a multitude of antiviral mechanisms. These include direct defensin targeting of viral envelopes, glycoproteins, and capsids in addition to inhibition of viral fusion and post-entry neutralization. Binding and modulation of host cell surface receptors and disruption of intracellular signaling by defensins can also inhibit viral replication. In addition, defensins can function as chemokines to augment and alter adaptive immune responses, revealing an indirect antiviral mechanism. Nonetheless, many questions regarding the antiviral activities of defensins remain. Although significant mechanistic data are known for α-defensins, molecular details for β-defensin inhibition are mostly lacking. Importantly, the role of defensin antiviral activity in vivo has not been addressed due to the lack of a complete defensin knockout model. Overall, the antiviral activity of defensins is well established as are the variety of mechanisms by which defensins achieve this inhibition; however, additional research is needed to fully understand the role of defensins in viral pathogenesis.

SignificanceWe report the development of peptidomimetic antibiotics derived from a natural antimicrobial peptide, human α-defensin 5. By engaging multiple bacterial targets, the lead compound is efficacious in vitro and in vivo against bacteria with highly inducible antibiotic resistance, promising a useful therapeutic agent for the treatment of infections caused by antibiotic-resistant bacteria.