Harnessing natural product diversity to combat multidrug-resistant pathogens

Antimicrobial resistance (AMR) constitutes one of the greatest threats to global public health. The leading AMR threats in South Africa (SA) reflect those on the WHO list of Critical/High Priority pathogens, which includes Gram-negative ESKAPE organisms, with growing levels of resistance to carbapenems and colistin. There is increasing concern over Sexually Transmitted Infections caused by resistant Neisseria gonorrhoea. There is a clear, unmet need for new agents to combat these bacterial pathogens. We will build on the extensive repertoire of SA and UK drug discovery expertise, with the aim of unlocking the potential resources contained in natural marine and terrestrial biota. In this work, we will have a strong emphasis on samples from SA, which is the 3rd most bio-diverse natural habitat on Earth and has the potential to deliver key natural product (NP)-derived antibiotics that are new to science and able to help meet the need for new antibiotics.

NPs are an unprecedented starting point for antibiotic discovery; NPs and their synthetic analogues are the sources of >80% of all clinically-utilised antibiotics. They represent the only validated source of chemical diversity capable of delivering a sustained pipeline of novel antibacterial drug candidates.

Our project consortium is a complementary, multi-disciplinary and balanced team of international experts in clinical/medical microbiology, natural product discovery, medicinal chemistry, antibiotic evaluation, biophysical analysis, bioinformatics, metagenomics, in silico discovery and molecular biology. Team members have successfully delivered multi-partner, multi-national research programmes and there are already established collaborations between SA and the UK within our group. Working together on this project will strengthen the current collaborations, forge new long-term relationships and further develop AMR drug discovery by building capacity for future research to explore the NP diversity in samples from SA and other locations and provide an on-going supply chain of new antibiotic leads.

In the integrated research projects proposed in this Hub, we will deploy new approaches for NP discovery, with an emphasis on samples selected from the highly diverse SA terrestrial and marine biota, which has yet to be systematically screened for antibacterial compounds. We will examine NP extract libraries that have not been mined for antibiotic candidates and we will also explore the hidden potential of microbes by mining metagenomic datasets and the genomes of cultured isolates. This approach will overcome many of the previous limitations of NP discovery, mitigating risks to maximise the potential for delivery of new antibiotic candidate hits.

We will conduct exchange visits for post doctoral researchers in both directions between SA and the UK and we will deliver a series of training workshops in both countries for PhD students and early career researchers. This will include training in basic sample collection and antimicrobial discovery methods, through to specialist training in NP characterisation and analysis tools, bioinformatics, lead optimisation, preliminary in vivo evaluation, PK/PD and entrepreneurship.

Our integrated programme of research and training across the UK and SA will draw on our expertise and access to diverse resources across our transnational network. Through the Hub activities, we will establish new infrastructure, expanding cutting-edge research capacity and we will comprehensively rejuvenate the discovery of novel antibiotics from NP sources.

Our consortium is committed to achieving our goal of identifying at least three characterised novel hit compounds that can be progressed to lead optimisation in future projects. We will target Gram-negative members of the ESKAPE group and Neisseria gonorrhoea, as these are among the leading AMR threats in South Africa.

We will work to achieve this aim by deploying interdisciplinary approaches for NP discovery on a wide range of samples, including those selected from the highly diverse SA terrestrial and marine biota, which has yet to be systematically screened for antibacterial compounds. We will examine NP extract libraries that have not been mined for antibiotic candidates and we will also explore the hidden potential of microbes by mining metagenomic datasets and the genomes of cultured isolates using in silico tools to identify biosynthetic gene clusters of interest for heterologous expression in recombinant hosts.

Promising hits will be characterised with respect to spectrum of activity, potency, prokaryotic selectivity, propensity for generating resistance, mode of action and in vivo efficacy in the Galleria mellonella infection model. The most encouraging hits will then be further analysed following rapid analogue production via synthesis alone, or by blending biosynthetic pathway engineering and synthetic chemical methodologies. This will allow hit optimisation and preliminary structure activity relationship investigation.

Through the Hub activities, we will establish new infrastructure, expanding cutting-edge research capacity and we will comprehensively rejuvenate the discovery of novel antibiotics from NP sources.

Impact on Society
The threat posed by antibiotic resistance is now widely publicised by a range of organisations including the UK Chief Medical Office, the WHO, the World Bank, the Infectious Disease Society of America and in the UK government's Review on Antimicrobial Resistance. Various statistics are reported by these bodies on the levels of resistance and the extent of the void in the antibiotic discovery pipeline, but all carry essentially the same message that a return to the pre-antibiotic era is almost inevitable for some bacteria and that the dire consequences of this are likely to affect all of humanity. The impacts of AMR are being felt most prominently in LMICs; South Africa is an Upper Middle Income country and has very high rates of resistance to some of the most critical threat pathogens, as determined by the WHO. Our entire medical system is supported by the therapeutic and prophylactic use of antibiotics, so losing them will have a profound impact on healthcare professionals who depend on the availability of effective antibiotics.
Given the scale of the issue and the fact that drug resistant infections can affect anyone, new antimicrobials arriving into the market have the potential for a profound impact in terms of improved health and longevity, social wellbeing and a reduction of the huge economic burden associated with infections caused by antibiotic resistant bacteria. With respect to ODA relevant research, the Hub activities will work towards addressing Sustainable Development Goals 1 (No poverty), 3 (Good Health and Well-being), 8 (Decent Work and Economic Growth) and 9 (Industry, Infrastructure and Innovation).

Scientific, Industrial and Clinical Impact
Discovery of novel antimicrobial compounds will sustain the pipeline of agents being developed towards the clinic, resulting in improved therapy of AMR infections into the future. A major limitation in the development of NP-derived antimicrobials, from certain sources, has been repeated recovery of known scaffolds. We are taking an integrated, multidisciplinary approach to explore new and diverse natural samples with rapid methods for de-replication and we will access the products of cryptic gene clusters. This will maximise the possibility of discovering new chemical entities and scaffolds for future development. The wider application of these approaches could have impacts outside the development of the antimicrobials that are the focus of this application and will be of interest to other industrial biotechnology or biopharmaceutical companies.

Training
Staff and students working in the Hub will benefit from the research and training programmes that will be delivered in the project. They will benefit through exposure to new techniques, publicising their findings at scientific meetings and in peer-reviewed publications and involvement in the translational aspects of the project, working with other partners in the consortium and with future commercial development partners. They will become part of the proposed NP Research Network and will form a cohort of researchers in NP drug discovery and development, helping to continue the supply of new compounds. Some may go on to be future leaders in their fields in SA and globally.