Antimicrobial resistance (AMR) is identified by the World Health Organisation (WHO) as an emerging global health threat, forecast to result in 10,000,000 deaths per year by 2050. The WHO and increasingly national and international agencies have flagged AMR as a priority theme and there is an urgent need for new antimicrobial agents and anti-infective strategies. Antimicrobial peptides (AMPs) are known to be potential alternatives to current/conventional antibiotics because of their specific physical and biological properties. AMPs are generally small cationic peptides produced by all living organisms (animals, plants, fungi or bacteria). Among their advantages, AMPs generally exhibit rapid bactericidal effects and they are active against current multiresistant strains (e.g. MRSA, ESBL E. coli etc). Limited widespread bacterial resistance to AMPs has been reported to date. In addition to having antimicrobial activity, some AMPs are key immune modulators and there has been much interest in exploiting this feature as an alternative mechanism for therapy of bacterial, viral or fungal infections. Accordingly, AMPs have been, and are still, well studied with more than 2900 AMPs described in the Antimicrobial Peptide Database (http://aps.unmc.edu/AP/main.php - June 2018). Nevertheless, only 28 AMPs are currently under-going pre-clinical-development or clinical trials, as described in the newly released Antibiotic DB (http://www.antibioticdb.com/ - June 2018) report, showing a real gap between the potential of AMPs and their effective application as therapeutics.
The main impediments recognized for the therapeutic use of AMPs are their high manufacturing cost, their unsatisfactory pharmacodynamics, and pharmacokinetics parameters as well as, for some peptides, their cytotoxicity and the risk of immunogenicity. However, some AMPs have performed well in clinical trials, but have not been approved by regulatory bodies. An obvious example is the topical formulation of Magainin, which demonstrated comparable efficacy to conventional systemic antibiotics for the treatment of diabetic foot ulcers. The FDA did not approve Magainin because it did not demonstrate superiority over conventional treatment, not because it was unsafe or ineffective.
Many AMPs that have reached clinical development have been isolated from microorganisms or are derived from AMP’s firstly isolated from microorganisms. AMP discovery from microorganisms has it’s own impediments and is particularly marked by the isolation of previously known compounds.
New approaches have been proposed to facilitate access to the native biodiversity of microorganisms and, therefore, potentially news AMPs. Approaches combining advances in genomic and transcriptomic technologies have also enabled rapid dereplication in AMP discovery. Biological synthesis and the downstream purification processes are being improved. New strategies have also emerged to counteract the impediments limiting the use of AMPs as therapeutic options. A notable effort has been given to (i) antimicrobial peptidomimetics that display extended stability in the presence of biological matrices (ii) AMP delivery systems (e.g. nanoparticles, polymeric materials).
The present Research Topic aims to publish articles demonstrating and seeking to address the gap between AMP discovery and AMP use as therapeutics. By exposing and gathering all new research and expert opinions on the AMP discovery process and their use as therapeutics, we hope that this Research Topic will inform future development of a rational pipeline of AMPs as a new generation of antibiotics and one of the few promising solutions to tackle AMR.
Antimicrobial resistance (AMR) is identified by the World Health Organisation (WHO) as an emerging global health threat, forecast to result in 10,000,000 deaths per year by 2050. The WHO and increasingly national and international agencies have flagged AMR as a priority theme and there is an urgent need for new antimicrobial agents and anti-infective strategies. Antimicrobial peptides (AMPs) are known to be potential alternatives to current/conventional antibiotics because of their specific physical and biological properties. AMPs are generally small cationic peptides produced by all living organisms (animals, plants, fungi or bacteria). Among their advantages, AMPs generally exhibit rapid bactericidal effects and they are active against current multiresistant strains (e.g. MRSA, ESBL E. coli etc). Limited widespread bacterial resistance to AMPs has been reported to date. In addition to having antimicrobial activity, some AMPs are key immune modulators and there has been much interest in exploiting this feature as an alternative mechanism for therapy of bacterial, viral or fungal infections. Accordingly, AMPs have been, and are still, well studied with more than 2900 AMPs described in the Antimicrobial Peptide Database (http://aps.unmc.edu/AP/main.php - June 2018). Nevertheless, only 28 AMPs are currently under-going pre-clinical-development or clinical trials, as described in the newly released Antibiotic DB (http://www.antibioticdb.com/ - June 2018) report, showing a real gap between the potential of AMPs and their effective application as therapeutics.
The main impediments recognized for the therapeutic use of AMPs are their high manufacturing cost, their unsatisfactory pharmacodynamics, and pharmacokinetics parameters as well as, for some peptides, their cytotoxicity and the risk of immunogenicity. However, some AMPs have performed well in clinical trials, but have not been approved by regulatory bodies. An obvious example is the topical formulation of Magainin, which demonstrated comparable efficacy to conventional systemic antibiotics for the treatment of diabetic foot ulcers. The FDA did not approve Magainin because it did not demonstrate superiority over conventional treatment, not because it was unsafe or ineffective.
Many AMPs that have reached clinical development have been isolated from microorganisms or are derived from AMP’s firstly isolated from microorganisms. AMP discovery from microorganisms has it’s own impediments and is particularly marked by the isolation of previously known compounds.
New approaches have been proposed to facilitate access to the native biodiversity of microorganisms and, therefore, potentially news AMPs. Approaches combining advances in genomic and transcriptomic technologies have also enabled rapid dereplication in AMP discovery. Biological synthesis and the downstream purification processes are being improved. New strategies have also emerged to counteract the impediments limiting the use of AMPs as therapeutic options. A notable effort has been given to (i) antimicrobial peptidomimetics that display extended stability in the presence of biological matrices (ii) AMP delivery systems (e.g. nanoparticles, polymeric materials).
The present Research Topic aims to publish articles demonstrating and seeking to address the gap between AMP discovery and AMP use as therapeutics. By exposing and gathering all new research and expert opinions on the AMP discovery process and their use as therapeutics, we hope that this Research Topic will inform future development of a rational pipeline of AMPs as a new generation of antibiotics and one of the few promising solutions to tackle AMR.
