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.