NPARI - Tailoring of novel peptide coatings and therapeutics derived from a newly identified component of the human innate immunity against resistant infections

EC contribution: : € 2.800.000
Duration: : 36 months
Starting date: : 01/12/2006
Funding scheme: : Specific Targeted Research Project
Keywords: : peptide, resistance, infection, antibacterial, antifungal, therapeutic agent, coating agent
Contract/Grant agreement number: : LSHM-CT-2006-037692
Project web-site: : http://npari.org/

Background:

The apoE and apoB human proteins have recently been linked to the innate immune system. Peptide sequences derived from these proteins have been shown to have varied anti-infective properties that can be modified by small changes to the core peptide sequence. Thus, the apoE and apoB peptides exhibit antibacterial, antifungal and antiviral properties, and present an excellent opportunity to develop novel therapeutics and medical device coatings.Specifically the exploitation of these novel peptides allows for the potential development of a new array of agents targeting against the growing problems of antibiotic resistant microorganisms.

Problem:

Infectious diseases represent the commonest cause of morbidity in the world (WHO). Over the last 40 years major advances have been made in the development of numerous classes of antimicrobial agents to treat serious life threatening infections. This is particularly true for antibacterial agents. However microorganisms are slowly turning the tide and becoming increasingly resistant to the agents developed by man. Long term and indiscriminate use of antibacterials has led to resistance developing for all the major classes of therapeutic agents. Increasingly clinicians are fighting a rearguard action with a dwindling armoury of drugs to combat serious life threatening infections. Nosocomial or hospital acquired infections (HAIs) represent an increasingly serious problem across Europe and the rest of the world.
Data from the SENTRY Antimicrobial Surveillance program of 25 European university hospitals highlighted the five most common bacterial blood isolates. The most prevalent organisms (E. coli, S. aureus, P. aeruginosa and K. pneumoniae) are also the most prevalent CVC associated infections (Clin Inf Dis 30; 3). Candida species were also common organisms isolated from blood and carried a crude mortality rate of up to 40%. These organisms are the same organisms where resistance is a major issue. The incidence of resistant bacterial and fungal nosocomial infections is high. The European Study Group on Nosocomial Infections (ESGNI) reports on blood stream infections indicated 72.8% of infections were nosocomial and mortality due to bacteremia was 7.1%. The most frequently isolated microorganisms from BSI were S. aureus (15.1%), E. coli (14.5%), S. epidemidis and coagulase negative staphs (CNS) (17.8%), P. aeruginosa /K. pneumoniae (both 5.3%) and Candida spp and enterococci (both 4.6%).(ESGNI-001, ESGNI-002).

Aim:

The aims of the NPARI consortium were to fully exploit the exciting properties of this novel peptide class. Specifically, the consortium aimed to target peptide sequences into two areas: coating agents for medical devices and therapeutics agents.
A major application for the apoE peptides is as coatings for medical devices such as catheters. ApoE derivative peptides are already in development as coatings for contact lenses. We aim to extend this application to use active peptides as coating agents for catheters. Catheter related infection causes significant morbidity and mortality across the EU and resistant bacteria and fungi are often responsible
Another focus for the application of apoE peptides is as therapeutic agents. We will focus on targeting specific resistant bacteria and fungi in order to rapidly establish in vivo efficacy in a variety of animal models. We will specifically target respiratory infections caused by Pseudomonas and Apsergillus. This will have direct clinical relevance to the 30,000 European CF patients where resistant Pseudomonas aeruginosa infections are a major cause of mortality. Colonisation with Aspergillus is also a major problem is this patient group.

Fig 1A: Resistance of apoE-coated hydrogels (at base of wells) to growth of P. aeruginosa. B. Bacteriolytic action against P. aeruginosa of hydrogels with concentrated stocks of apoE (and thoroughly washed prior to bacterial challenge).

Expected and obtained results:

The design of a small peptide library tailored to the proposed exploitable application of the project.
Determination of the activity spectrum of active peptides and ranking of peptide variants.
Optimisation and toxicity profiling of active peptides.
Efficacy profiles against a panel of resistant organisms growing as biofilms.
Pharmacological and efficacy evaluation of peptides in a range of models.
Efficacy data for candidate coatings in dynamic biofilm models.

Potential applications:

The exploitation of this new class of antimicrobial peptides offers the potential to develop new therapeutics against a range of the most resistant and problematic organisms facing European infectious disease clinicians. The rate infection by resistant bacteria is increasing but new chemical agents are some way from the clinic. This project aims to develop candidate peptide therapeutics which target the most problematic organisms and develop them to the point were they show sufficient potential for further development.

In addition the project focuses on the prevention of infection by the same resistant organisms through the coating of medical devices with active peptides.
By preventing the colonisation of catheters by resistant microorganisms it is expected that serious life threatening infections can be avoided.SME Participation

A vital component to the project is the participation of several small and medium-sized enterprises (SMEs) who have expertise in the fields of drug development. This, combined with the academic expertise of the remaining partners, allowed for an experienced and focused consortium.
Nikem Research are an Italian based company who specialise in drug development. Nikem have a wide range of ADMET and toxicological assays which can be applied to the project. In addition Nikem have a range of bioanalyical capabilities which will be employed to monitor the pK/pD profiles of the peptides.
Similarly F2G has expertise in the discovery and development of anti-infective agents, specialising in anti-fungals. With a range of HTS screening capabilities, chemistry and pharmacology experience, F2G is able to rapidly assess and develop peptides in to therapeutic candidates.
The focus of Ai2 is on the use of peptides to prevent colonisation of medical devices which complements well the expertise within the consortia.

Coordinator:

Dr Mike Birch
F2G Ltd
Po Box 1, Lankro Way
Eccles
Manchester, M30 OBH
England, UK
Tel. +44 161 785 1277
Fax +44 161 785 1273
E-mail: mikebirch@f2g.com

European Commission