Targeted natural product diversification to identify novel antibacterial agents

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Abstract With the advent of the “age of antibiotics” in the 1940s, many believed that we had conquered these dangerous microbes. However, it quickly became apparent that the ability of bacteria to evolve resistance had been sorely underestimated and today, infectious diseases are the second-leading cause of death worldwide and the third-leading cause of mortality in economically advanced countries. The ever-growing and significant problem of antibacterial resistance requires discovery of new leads. However, identification of the next generations of antibiotics will necessitate a change in the current drug discovery paradigm. Pursuit of compounds that function through the commonly targeted mechanisms of action will not yield the combination of antibiotic potency and long-term efficacy necessary to combat resistant organisms. In fact, compounds that attack microbes through multiple, simultaneous mechanisms will be essential to anti-infective development. Given the anticipated therapeutic benefits of modulation of bacterial virulence and host innate immunity, we will focus our efforts on the identification of compounds possessing these activities. The proposed work will facilitate discovery of antibacterial agents by transforming the ways in which natural product are both explored and exploited. Although natural products have historically provided the majority of treatments for infectious disease, the exceptional potential of nature's molecular repertoire is still largely untapped because the current approaches used in their discovery are fundamentally limited in both scope and power. Thus, there is tremendous need for development of methods that can investigate the confluence of natural product space and antibiotic space. To accomplish this goal, we will apply our chemoselective natural products isolation technology, which facilitates compound enrichment by reversible capture of a specified functional group class onto solid support, to the exploration of natural products. This tagging technology will also be utilized in the creation of a novel natural product diversification strategy. Existing approaches for natural product library generation depend upon the functionalization of discreet natural products, a process that is influenced by both the choice of lead structure and preconceptions about how derivatization will affect activity. We will devise a method for discovery that is not biased by existing hypotheses. Following chemoselective immobilization, derivatization of the natural products will be performed in an unbiased fashion; that is, we will perform functionalization reactions without prior knowledge of the natural product structures. Derivatization of the natural products with targeting agents, such as a virulence mechanism inhibitor, will yield a diverse library of compounds containing a known bioactive portion and a novel natural product moiety. This approach will facilitate the identification of dual-function compounds with enhanced anti-infective properties.