Despite the notable success of antibiotics, bacterial diseases remain the second-leading cause of mortality worldwide, causing 17 million deaths globally. One of the most significant public health concerns in the context of infectious disease is the continued and rapid emergence of drug resistant bacteria during antibiotic treatment. As such, there is an undeniable and desperate need to develop new antibacterial therapeutics to fight multi-drug resistant infections. Indeed, the pace of drug resistance has outstripped the discovery of new antimicrobial agents, creating an urgent need for new antibiotics with novel mechanisms of action. Natural products have played a major role in antibiotic chemotherapy, beginning with penicillin in 1941, and followed by a litany of other trusted agents over the ensuing decades. In the last twenty-five years alone, natural products have inspired more than 75% of small molecule antibiotics, and two of only three new antibiotic classes approved in the last forty years. A major concern, however, is that natural product based divining for new lead agents is becoming increasingly difficult. This is largely believed to result from the comprehensive mining of available producing organisms, and a relatively complete understanding of their metabolic pathways. However, it is also widely projected that the wealth and availability of compounds produced by environmental microorganisms has actually been sorely underestimated, in large part because many biosynthetic pathways are silent under laboratory growth conditions. In this study, we propose to take the novel, but precedented, approach of epigenetically modifying a unique library of marine-margin endophytic fungi to trigger production of latent and cryptic metabolites. These organisms are ideal for use in such a project as they are almost entirely untapped in the context of antibacterial drug discovery, whilst at the same time possessing inherently complex secondary metabolomes. As such, we seek to unlock dormant metabolic pathways in our fungal isolates via epigenetic manipulation, for the exploitation of new secondary metabolites that possess antibacterial activity. This will be achieved by: 1. The production, purification and structural analysis of natural product lead compounds.
This aim will provide chemodiversity for screening, derived from endophytic fungi cultivated both with and without epigenetic modifiers. Antibacterial extracts derived from these cultures will be isolated, purified and their structures determined. Novel chemotypes retaining favorable bioactivity will then further characterized by: 2. A comprehensive activity and toxicity profiling of lead agents. In this aim we will perform a prioritized and rationalized analysis of led agents by determining their antibacterial spectrum of activity against multi-drug resistant ESKAPE pathogens, their cytotoxic effects towards eukaryotic cells, their anti-biofilm properties, and the potential for bacterial resistance to their effects. We contend that our preliminary work;coupled with novel approaches, give our project a very high chance of yielding new and novel chemical scaffolds for future antibiotic development.
The World Health Organization has identified antimicrobial resistance as one of the three greatest threats facing mankind in the 21st century. As such, there is an undeniable need to develop new therapeutics to fight multi-drug resistant bacterial infections. This application addresses this need, by using a novel epigenetic manipulation method as a tool for discovering new antibacterial lead compounds.
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