Assessing the relevance of Galleria mellonella to antibiotic drug discovery for pulmonary infections
Lead Research Organisation:
King's College London
Department Name: Pharmaceutical Sciences
Abstract
As we are all increasingly aware, the world faces the renewed threat of bacterial infections due to the rise in cases where bacteria are resistant to the antibiotics that are normally used to treat such infections. Ongoing efforts to counter this threat are wide-ranging but two key elements are: 1) the discovery of new classes of antibiotic and; 2) the understanding how bacteria adapt to both antibiotics and antiseptics so that appropriate responses can be devised and enacted.
The Institute of Pharmaceutical Science at King's College London is a hub of research activity in these two areas. Together with the National Infection Service of Public Health England and other partners, we have identified four new classes of antibiotic that have the potential to be effective against the most troubling, antibiotic resistant bacteria currently causing infections in patients. We have also taken steps to understand how these same bacteria adapt to antiseptics that are used in hospitals. We have shown that this can happen, but not whether it does and have not yet discovered if bacterial adaptation to antiseptics makes the bacteria tougher or weaker.
The key steps in moving this research from bench to bedside is to have effective infection models so we can test if your antibiotics are likely to work in patients or know if infections are likely to be more or less severe if bacteria adapt to antiseptics. Normally this work would be done in mice and we have tried and tested models of bacterial lung infection which simulate the kind of infections patients might get e.g. when ventilated in hospital.
Data from these models is widely regarded as robust and relevant to both human and other mammalian infections (hence they also have application in veterinary science). However, these models are expensive, require highly trained staff and their use for screening many compounds/conditions is inappropriate. Consequently there is a bottleneck in both research areas and an ethical, cost effective and predictive alternative that can be used even by laboratories that do not specialise in animal studies is highly desired.
Caterpillars of the greater wax moth have been used by some groups elsewhere to replace mice in models of bacterial infection. Although many people are much more comfortable with the use of caterpillars for research rather than mice or other animals, of course caterpillars do not have lungs and so there is a perception that this model may not be relevant to lung infections in humans (or pets or livestock). Nevertheless, some early tests with caterpillars looked promising and have generated some excitement that caterpillars are indeed an appropriate model that can reduce testing in mice. However a further problem has arisen: often the bacteria that are the biggest problem in lung infections were too toxic to the caterpillars and the infection model for these key bacteria was not really useful.
This project aims to break down these perceived and real barriers to adoption of the caterpillar infection model. We will use a special research grade of caterpillar provided by a new company spun-out from Exeter University which is expected to give more reliable results. While establishing this technology at King's we will adapt it for our purposes by modifying how we grow bacteria and also getting bacteria accustomed to living in the caterpillar host. When we have done this we will act as a hub to share our know-how with our partners and other researchers worldwide.
The Institute of Pharmaceutical Science at King's College London is a hub of research activity in these two areas. Together with the National Infection Service of Public Health England and other partners, we have identified four new classes of antibiotic that have the potential to be effective against the most troubling, antibiotic resistant bacteria currently causing infections in patients. We have also taken steps to understand how these same bacteria adapt to antiseptics that are used in hospitals. We have shown that this can happen, but not whether it does and have not yet discovered if bacterial adaptation to antiseptics makes the bacteria tougher or weaker.
The key steps in moving this research from bench to bedside is to have effective infection models so we can test if your antibiotics are likely to work in patients or know if infections are likely to be more or less severe if bacteria adapt to antiseptics. Normally this work would be done in mice and we have tried and tested models of bacterial lung infection which simulate the kind of infections patients might get e.g. when ventilated in hospital.
Data from these models is widely regarded as robust and relevant to both human and other mammalian infections (hence they also have application in veterinary science). However, these models are expensive, require highly trained staff and their use for screening many compounds/conditions is inappropriate. Consequently there is a bottleneck in both research areas and an ethical, cost effective and predictive alternative that can be used even by laboratories that do not specialise in animal studies is highly desired.
Caterpillars of the greater wax moth have been used by some groups elsewhere to replace mice in models of bacterial infection. Although many people are much more comfortable with the use of caterpillars for research rather than mice or other animals, of course caterpillars do not have lungs and so there is a perception that this model may not be relevant to lung infections in humans (or pets or livestock). Nevertheless, some early tests with caterpillars looked promising and have generated some excitement that caterpillars are indeed an appropriate model that can reduce testing in mice. However a further problem has arisen: often the bacteria that are the biggest problem in lung infections were too toxic to the caterpillars and the infection model for these key bacteria was not really useful.
This project aims to break down these perceived and real barriers to adoption of the caterpillar infection model. We will use a special research grade of caterpillar provided by a new company spun-out from Exeter University which is expected to give more reliable results. While establishing this technology at King's we will adapt it for our purposes by modifying how we grow bacteria and also getting bacteria accustomed to living in the caterpillar host. When we have done this we will act as a hub to share our know-how with our partners and other researchers worldwide.
Technical Summary
The study of respiratory disease, particularly bacterial lung infections, is an established theme within the Institute of Pharmaceutical Science (IPS) at King's which works closely with the Technology Development Group, National Infection Service, Public Health England. Seven PIs (Page, Pitchford, Bruce, Rahman, Castagnolo, Panaretou and Mason) are active researchers in this field, providing expertise in mammalian models of lung infection (Page, Pitchford), small molecule (Rahman, Castagnolo) and peptide (Mason) drug discovery, microbiome (Bruce, Mason) and fungal genetics (Panaretou).
Page and Pitchford have established models of EMRSA-15 and Pseudomonas aeruginosa RP-73 acute lung infection and it is being developed further to enable study of multi-species biofilms. These models are being used or will imminently be used to evaluate four new classes of antibiotic as well as understand the effect on virulence of adaptation and resistance to antimicrobials.
While these models are attractive and provide very compelling data relevant to human and mammalian infection, they are expensive, require highly trained staff and their use for screening many compounds/conditions is inappropriate. An ethical, cost effective and predictive alternative that can be used routinely even in those laboratories that do not specialise in animal studies is highly desirable.
Galleria mellonella is an emerging technology whose utility in many of these areas has been demonstrated but there are perceived, and some real, barriers to is wider adoption. TruLarv are research grade larvae that are expected to provide inherently more reliable data. Trained in its use by Biosystems technology, we will establish this technology in all eight research groups at King's and PHE, evaluate and adapt it - notably for the study of P. aeruginosa RP73 - and disseminate our experience and know-how to partners and other end users to foster its wider adoption.
Page and Pitchford have established models of EMRSA-15 and Pseudomonas aeruginosa RP-73 acute lung infection and it is being developed further to enable study of multi-species biofilms. These models are being used or will imminently be used to evaluate four new classes of antibiotic as well as understand the effect on virulence of adaptation and resistance to antimicrobials.
While these models are attractive and provide very compelling data relevant to human and mammalian infection, they are expensive, require highly trained staff and their use for screening many compounds/conditions is inappropriate. An ethical, cost effective and predictive alternative that can be used routinely even in those laboratories that do not specialise in animal studies is highly desirable.
Galleria mellonella is an emerging technology whose utility in many of these areas has been demonstrated but there are perceived, and some real, barriers to is wider adoption. TruLarv are research grade larvae that are expected to provide inherently more reliable data. Trained in its use by Biosystems technology, we will establish this technology in all eight research groups at King's and PHE, evaluate and adapt it - notably for the study of P. aeruginosa RP73 - and disseminate our experience and know-how to partners and other end users to foster its wider adoption.
Planned Impact
Since the aim of this project is to introduce, evaluate and refine the TruLarv infection model and disseminate knowledge obtained from this process. The immediate impact will be felt at King's with longer term impacts emanation through King's PIs and their partners. Most notably, the broad-spectrum attributes of four emerging classes of antibiotic can be tested, with only proof of concept experiments require in mice. This will accelerate hit-to-lead, lead optimisation and some formulation elements of the antibiotic drug discovery process - all achieved while reducing and replacing studies in mice. For research that is at an earlier stage, greater relevance can be easily demonstrated by routinely moving from in vitro to infection models. With the critical mass of lung-infection researchers in IPS at King's, the team will emerge as a hub for further development of alternative research models for lung infection research.
The project underpins a wider programme of research that will have wide-ranging economic, animal and public health benefits in the longer term. These will arise from the creation of new and enduring classes of antibiotic, a better understanding of how bacteria adapt to antimicrobials and the effects that this will have. Notably, the O'Neill reports state that "...failing to tackle drug-resistant infections will cause 10 million deaths a year and cost up to US$ 100 trillion by 2050." The outcomes of this project will make a substantial contribution to mitigating this threat by accelerating antibiotic drug discovery and (to an extent) formulation. This will stimulate the discovery of new antibiotics and antibiotic combinations which will be effective in the face of bacteria carrying existing resistance determinants and help in developing new ways of monitoring and reacting to the emergence of resistance to antibiotics and/or antiseptics.
The project underpins a wider programme of research that will have wide-ranging economic, animal and public health benefits in the longer term. These will arise from the creation of new and enduring classes of antibiotic, a better understanding of how bacteria adapt to antimicrobials and the effects that this will have. Notably, the O'Neill reports state that "...failing to tackle drug-resistant infections will cause 10 million deaths a year and cost up to US$ 100 trillion by 2050." The outcomes of this project will make a substantial contribution to mitigating this threat by accelerating antibiotic drug discovery and (to an extent) formulation. This will stimulate the discovery of new antibiotics and antibiotic combinations which will be effective in the face of bacteria carrying existing resistance determinants and help in developing new ways of monitoring and reacting to the emergence of resistance to antibiotics and/or antiseptics.
