MICA: Revisiting unexploited natural product antibiotics in the fight against multidrug-resistant bacterial pathogens

The clinical introduction of antibiotics in the early years of the 20th century enabled for the first time the treatment and cure of bacterial infections, and heralded a new era for humanity. However, the usefulness of these agents has become steadily eroded as disease-causing bacteria have evolved to resist their effects, and we have now reached a point where bacterial infections can prove difficult, sometimes even impossible, to treat. Unless new antibiotics are developed as a matter of urgency, we face untreatable bacterial infections on a scale not seen since the pre-antibiotic era, a time when death from bacterial infection in otherwise-healthy individuals was common. Indeed, infections caused by antibiotic-resistant bacteria now represent one of the most pressing areas of unmet medical need, and the World Health Organization has declared the problem one of the top three currently facing human health.

The present proposal aims to investigate in detail five natural products (chemicals produced by microorganisms) for their potential to be developed into new antibiotics for treating bacterial infections in humans. Natural products have been rather overlooked in recent years as a potential source of new antibiotics, since a considerable proportion of antibiotic discovery and development has focused on trying to make new synthetic (man-made) antibiotics. However, in view of the fact that natural products are the source of the majority of antibiotics already in clinical use, we believe that they likely also represent the best source of new antibiotics. To maximize the likelihood that our natural products can be developed into antibiotic drugs for treating infection, we have chosen to pursue only those for which there is already some evidence in the scientific literature that they are effective against bacterial infection in animals. This approach effectively means that these natural products have already overcome many of the most significant hurdles that stand in the way of developing chemical compounds into safe and effective drugs to treat infection.

We propose to prepare the five natural product antibiotics from their producing microorganisms, examine in detail their ability to effectively inhibit the growth/kill bacteria and establish how they do this, and confirm that they are safe and effective in models of bacterial infection. The results of these studies will provide important fundamental scientific knowledge, and will establish whether one or more of these natural products are suitable for further development into antibiotic drugs. The project will be conducted in collaboration with Cubist Pharmaceuticals, an industry-leader in natural product antibiotics; by harnessing complementary strengths and capabilities in antibiotic research within academia and industry, we aim to establish a synergistic partnership capable of progressing these novel antibiotics from bench to bedside.

Resistance to antibacterial drugs among bacterial pathogens severely compromises our ability to treat and cure the infections that they cause, and represents one of the greatest problems currently facing human health. Novel antibacterial drugs are now urgently required, but owing to a confluence of factors, antibacterial drug discovery and development has all but stalled. The present proposal outlines an approach that seeks to deliver novel antibacterial drug candidates into the development pipeline. This approach is characterized by (i) a re-focus on natural product antibiotics, the source of the overwhelming majority of antibacterial drugs in clinical use, and (ii) the decision to pursue only unexploited antibiotic classes which have demonstrated in vivo activity against bacterial pathogens in animal models, a strategy that will circumvent many of the problems encountered in recent antibacterial drug discovery/development programmes. Building on preliminary studies, we propose to ferment and purify five promising natural product antibiotics in sufficient quantities to enable their downstream characterization, conduct a full evaluation of their microbiological activities and modes of action, and examine their pharmacological profiles (including pharmacokinetics, toxicity and in vivo efficacy in mice). Results gained from these studies will provide important fundamental scientific knowledge, and will establish whether one or more of these compounds are suitable for further clinical development and/or chemical improvement. The project will be conducted in collaboration with Cubist Pharmaceuticals, an industry-leader in natural product antibiotics; by harnessing complementary strengths and capabilities in antibiotic research within academia and industry, we aim to establish a synergistic partnership capable of progressing these novel antibacterial drug candidates from bench to bedside.

Potential benefits of the proposed research outside of the academic sector are as follows;

(i) Social and economic benefits. In the short term, the proposed work will serve to build UK capacity and expertise within a field extremely important to human health, and one that has been in significant decline - antibacterial drug development, and particularly, natural product antibiotics. The training the PDRA would receive, provided within a unique multi-disciplinary, translational and intersectoral format, would deliver a highly-skilled researcher with excellent employment prospects in either academia or industry. The proposed project will forge an international academic-industrial partnership with the potential to develop additional, future projects to identify and rapidly progress antibacterial drug candidates.

Longer term, the project aims to deliver novel antibacterial drug candidates into the development pipeline, and ultimately into the clinic, to address the rapidly escalating problem of untreatable bacterial infections caused by multidrug (MDR)-resistant bacteria. Since such infections now represent one of the most pressing areas of unmet medical need, and the World Health Organization has declared antimicrobial drug resistance one of the three greatest problems currently facing human health, successful delivery of this aim would have a considerable positive impact on the quality of life and health in the UK and worldwide. The generation of associated IP and revenue would contribute to global economic performance, and where the IP is developed at Leeds, would specifically contribute to the economic competitiveness of the UK.

(ii) Benefits to industry: In the immediate term, the proposed collaboration will provide the industrial partner (Cubist) with access to complementary expertise and technologies not available to them in industry, and the opportunity to evaluate for progression several promising antibacterial drug candidates of which they had not previously been aware. Longer-term, the proposed study should yield knowledge that will be of importance and interest to the field of antibacterial drug discovery and development, both in academia and industry. In particular, successful delivery of novel antibacterial drug candidates through the proposed study would not only provide validation for natural products as a current and future source of antibacterial drug candidates, but offer further corroboration for the strategy of revisiting unexploited antibacterial agents in search of potential drug candidates. Finally, the unique training received by the PDRA in this study would not only benefit the UK through delivery of a highly-skilled researcher, but could benefit industry; the skill-set acquired by the PDRA during this project would make them highly sought-after in the industrial sector.