Abstract Description

Antimicrobial resistance (AMR) has emerged as a bigger killer in Africa than malaria, HIV or tuberculosis. Current antibiotic drug development pipelines are insufficient to combat the AMR threat. Finding new classes of antibiotics, particularly those with new modes of action to combat multi-drug resistant bacteria is considered of paramount global health importance. In this presentation, we report five Actinobacteria isolated from the Marion Island terrestrial environments; Streptomyces spp. MIAP_724B, MIAP_721B, Streptomyces microflavus MIAP_270B, Leifsonia sp. MIAP_437 and Agrococcus sp. MIAP_691 which were prioritized based on the in vivo antibacterial activities against a panel of ESKAPE-E pathogens and/or in vitro inhibition of bacterial 6-Hydroxymethyl-7,8- dihydropterin pyrophosphokinase (HPPK) and 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR) activities. Using whole genome analysis and untargeted metabolomics approaches, we dereplicated and characterized the metabolites in active natural product (NP) extracts, allowing the putative identification of known antimicrobial compound classes including neomycins, bafilomycins and polycyclic tetramate macrolactams, and their as yet uncharacterized derivatives. Finally, using the Tanimoto approach, we mapped 24 biosynthetic gene clusters to features in a molecular network, of which six were matched to compounds they are predicted to synthesize, while the remainder mapped to unknown potentially novel compounds and/or derivatives of known compounds. These findings advance the field of NPs discovery, highlighting the hidden potential of Actinobacteria native to Marion Island and providing potentially novel lead compounds for the discovery of new classes of antibiotics.