Antimicrobial peptides – evolution’s answer to microbial resistance?
Jan Alenfall
DermaGen AB
Antimicrobial peptides (AMPs) are an ancient group of defence molecules. They display multiple modes of action, such as bactericidal, fungicidal and cytolytic properties, as well as having immunomodulating properties.
These peptides are found in virtually all life forms where they work as a rapid and non-specific immunity, used as a first line of defence against invading pathogens. Evolution has created and fine-tuned AMPs to act against dangerous microbes. Despite co-evolution with microbes over millions of years, AMPs have retained their advantage and microbes have yet to find any resistance to their potent effects.
Today, microbial resistance is a major problem, limiting the usefulness of traditional antibiotics. The need for new alternatives was recently highlighted by the European Centre for Disease Prevention and Control (ECDC)/ European Medicines Agency (EMEA) joint technical report1. As Dominique Monnet, responsible for the ECDC part of the study, stated, “A future without effective antibiotics will exacerbate a situation where already at least 25,000 patients in the EU each year die from infections due to multidrug-resistant bacteria. Patients suffering from healthcare-associated infections will be particularly hard hit.”
"A future without effective antibiotics will exacerbate a situation where already at least 25,000 patients in the EU each year die from infections due to multidrug-resistant bacteria."
In the face of this challenge, AMPs have the potential to become an important new class of drug to be added in the armamentarium against microbes. At the same time, they may also represent the long-awaited breakthrough in defeating microbial resistance.
The need for new anti-infectives
The dramatic increase in resistance towards classical antibiotics by certain microorganisms has created a major medical need for new anti-infective products. For example, more than 50% of Staphylococcus aureus isolates found in Sweden are resistant to fusidic acid and in many other countries the situation is even worse.
Within the dermatology market, anti-infective treatments represent the largest segment, accounting for approximately 31% of the entire market value. Continued growth is expected in the anti-infectives market where new broad-spectrum, multi-indication agents typically have huge potential shortly after market introduction.
It is surprising, therefore, that few anti-infective products have been developed by major pharmaceutical companies in recent years. In fact, a reduction in new antibacterials in the development pipeline has been noted, with new agents struggling to demonstrate the required efficacy and low toxicity. One reason for this may be today’s more demanding regulatory environment, with a focus on clear evidence of “superiority” to existing agents, rather than “non-inferiority”. However, historically the success rate in for anti-infectives in clinical trials (measured at phase II) has been at around 80%, compared to a market average of ~40%2, and these agents are often quick to reach the market.
As such, an opportunity exists for smaller companies that are able to concentrate their efforts on creating new topical products and/or prolonging the patent life of current products.
The role of AMPs
The discovery of AMPs dates back around 80 years to the time when lysozyme was discovered. More recently, numerous AMPs have been found in insects, frogs and human neutrophils, creating a surge of interest and an explosion in related publications.
A review of the literature demonstrates that all organisms mount an effective and rapidly acting molecular defence in response to invading pathogens. AMPs also provide a range of non-antimicrobial bioactivities related to defence, inflammation and wound healing. Most AMPs are gene encoded short peptides, less than 50 amino acids in length.
Human innate immunity comprises various AMPs depending on location. For example, AMPs are ubiquitously distributed in epithelial surfaces and mount an effective and rapidly acting defence as an early response to invading pathogens. At some locations this is partly mediated by continuous expression of AMPs in a variety of different cells, such as in skin and in the gastrointestinal tract – in other words, providing an active ongoing biochemical defence against potential pathogens. AMPs are also found stored in granules in neutrophils to be released when needed. Today, more than 900 AMPs from various sources are described in databases.
Most AMPs are rapid-acting and potent, possessing an unusually broad spectrum of activity. Consequently, they have prospects as new antibiotics, although hitherto clinical trials have shown efficacy only as topical agents.
Many companies are active in pursuing regulatory approval of new AMPs. However, to achieve their therapeutic potential and overcome clinical setbacks, further work is needed to understand their mechanisms of action, reduce the risk of toxicity and to make them more resistant to protease degradation, in order to improve serum half-life. In addition, suitable methods for large-scale, cost-efficient manufacturing are also needed.
The potential role of AMPs needs to be considered in context with the current healthcare situation, where multiresistant bacteria, such as MRSA and VRE, are causing serious problems. In hospitals these bacteria typically give rise to nosocomial infections, which are difficult to treat with conventional antibiotics. The increasing development of resistance to antibiotics, potential toxic effects and allergy problems form the major obstacles in the development of new antimicrobial therapies.
"...the lack of microbial resistance development to AMPs should be considered an important factor when making comparisons to existing agents..."
As such, the question has to be asked whether a new antibacterial agent, that avoids microbial resistance but only shows evidence of “non-inferior” efficacy, should still be considered a valuable drug? In the author’s opinion, the lack of microbial resistance development to AMPs should be considered an important factor when making comparisons to existing agents, particularly in the development of treatments for topical use.
Clinical opportunities for AMPs
There is little doubt that AMPs represent product concepts with broad applicability. However, while examination of these peptides has shown general trends in physiochemical parameters, little sequence homology is found. This suggests that each AMP has evolved to act optimally against local microorganisms in the environment in which it is produced.
As such, it is tempting to suggest that it is important to select and develop AMPs that already occur at the site of infection or in close vicinity to the disease area. By manipulating the peptide structure and optimizing pharmaceutical formulation it is possible to create designer peptides for achieving specific antimicrobial and biological effects. The advantage being, in contrast to classical antibiotics, that such AMPs are unlikely to induce any resistance because they have co-evolved with the target pathogens and lack a specific molecular target on bacteria or other microbes.
Let us consider atopic dermatitis (AD) as an example indication for an AMP-based therapy. AD is a chronic inflammatory skin disease, affecting people of all ages, in which dry skin and the skin’s weakened barrier function make patients susceptible to irritants and other external trigger factors – one of the most common being microorganisms. Around 90% of all AD patients are colonized or infected by the gram-positive bacterium Staphylococcus aureus (S. aureus), whereas only about 5% of healthy individuals harbour the bacterium. Infection with S. aureus seriously aggravates the disease by producing superantigens that induce inflammation of the skin and exacerbate associated symptoms.
Although systemic therapies are available, especially for severe AD, topical treatments form the vast majority of therapies. Steroids, in the form of creams, ointments, lotions, gels and foams, are currently the most common treatment for AD. They are available in various potencies and their anti-inflammatory and anti-pruritic action is well-proven. However, topical corticosteroids, for example, are associated with side effects, including atrophy, fragility of the skin, fragile skin blood vessels and poor wound healing. Steroids may also induce allergy. As such, they are generally used as short-term therapy (days to weeks), and in combination with other drugs.
Modern topical calcineurin inhibitors, immunomodulators, are used in combination with, or, as alternatives to steroids. However, safety concerns leading to black-box warnings have significantly decreased the attraction of these drugs. Systemic and topical antibiotics are currently used to treat secondary infections, even though the number of resistant strains keeps increasing. There are presently no suitable topical antibiotics for long-term or prophylactic treatment.
"An AMP-based therapy represents a very attractive biological approach to reduce the microbial load and, thus, potentially reduce the severity of the disease."
It has been established that the local presence of AMPs in the eczemas of AD patients is severely depressed, which may explain the high-level colonization of microbes. The presence of microbes may also reduce the effects of common steroid and immunomodulator therapies. In this situation, an AMP-based therapy represents a very attractive biological approach to reduce the microbial load and, thus, potentially reduce the severity of the disease.
Development approach
DermaGen is developing a novel AMP derived from a natural endogenous human protein. This approach provides little risk of provoking an immune response, inducing allergy or of microbial resistance development. It is anticipated that an initial product indicated for atopic dermatitis will provide a safe and effective treatment option, either as a single therapy to minimize long-term microbial influence on the disease or in combination with other drugs. The product may also be effective in many other uncomplicated skin infections or as prophylaxis, e.g. post-surgery.
The project is currently in clinical development, where promising results have been achieved to date.
Future projects will be based on DermaGen’s strong technology platform, which makes it possible to fine-tune AMPs and optimize pharmaceutical formulations in order to specifically target commercially interesting indications.
Numerous opportunities exist for the topical treatment and prevention of a wide range of dermatological bacterial and fungal infections, including impetigo and infected wounds and burns. Opportunities also exist for extending the patent life of existing antimicrobial products.
The strategy for developing new AMPs should focus on delivering unique capabilities and a broad antibacterial spectrum, tailored for effective control of the bacterial flora at various locals. Synthetic peptides can also be designed to improve factors such as specificity, stability, and toxicity.
An AMP development program should consider the following important factors:
• High therapeutic index
• Broad spectrum of activity
• Demonstrated effect in formulation with high chemical stability
• Safety with demonstration of few side effects
• Minimal risk of microbial resistance
• Minimum of allergy induction
• Availability for all patient groups, including infants
• Opportunity for long-term and prophylactic use
• Favourable Cost of Goods
Conclusions
The antibacterial market is set for a period of significant change. Key products are facing patent expiry, the rise of resistant pathogens is posing increasing difficulties and the increasing severity of infections within hospital populations is a serious concern. As such, current products will face tough challenges to maintain sales and market growth will be driven by novel approaches.
AMPs represent one such novel approach. In addition to their potent antimicrobial properties their evolutionary path addresses the issue of microbial resistance head on. The use of topically administered AMPs for control and normalization of bacterial and fungal flora represents a logical and attractive therapeutic approach.
Through the fine tuning of AMPs, specific antimicrobial and biological effects can be achieved. Although a good deal of development work still remains, it is looking increasingly likely that AMPs have the potential to offer safe and effective treatments across a wide range of indications without the risk of microbial resistance development.
References:
1. ECDC/EMEA Technical Report “The bacterial challenge, time to react”, http://www.emea.europa.eu/pdfs/human/antimicrobial_resistance/EMEA-576176-2009.pdf
2. Deloitte &, Touche Pan European Mediscience Review 2002, page 55
About the author:
Dr. Jan Alenfall is CEO of DermaGen AB, based in Sweden. For enquiries regarding this article he may be contacted at jan.alenfall@dermagen.se.
About DermaGen AB
DermaGen develops peptide therapeutics for topical use based on novel and proprietary antimicrobial peptides (AMPs). It intends to be a leading R&,D company in this area with the aim of offering innovative and profitable licensing opportunities to selected pharmaceutical companies with significant market potential. DermaGen focuses on R&,D to provide new and patented products initially for dermatological indications. For more information please visit .
What role do you think AMPs can play in managing infection and could they represent a solution to increasing antibiotic resistance?
