With the advent of the age of antibiotics in the 1940s, many believed that we had conquered thesedangerous microbes. However, it quickly became apparent that the ability of bacteria to evolve resistance hadbeen sorely underestimated and today, infectious diseases are the second-leading cause of death worldwideand the third-leading cause of mortality in economically advanced countries. The ever-growing and significantproblem of antibacterial resistance requires discovery of new leads. However, identification of the nextgenerations of antibiotics will necessitate a change in the current drug discovery paradigm. Pursuit ofcompounds that function through the commonly targeted mechanisms of action will not yield the combination ofantibiotic potency and long-term efficacy necessary to combat resistant organisms. In fact, compounds thatattack 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 willfocus our efforts on the identification of compounds possessing these activities. The proposed work will facilitate discovery of antibacterial agents by transforming the ways in whichnatural product are both explored and exploited. Although natural products have historically provided themajority of treatments for infectious disease, the exceptional potential of nature's molecular repertoire is stilllargely untapped because the current approaches used in their discovery are fundamentally limited in bothscope and power. Thus, there is tremendous need for development of methods that can investigate theconfluence of natural product space and antibiotic space. To accomplish this goal, we will apply ourchemoselective natural products isolation technology, which facilitates compound enrichment by reversiblecapture of a specified functional group class onto solid support, to the exploration of natural products. Thistagging 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 naturalproducts, a process that is influenced by both the choice of lead structure and preconceptions about howderivatization will affect activity. We will devise a method for discovery that is not biased by existinghypotheses. Following chemoselective immobilization, derivatization of the natural products will be performedin an unbiased fashion; that is, we will perform functionalization reactions without prior knowledge of thenatural product structures. Derivatization of the natural products with targeting agents, such as a virulencemechanism inhibitor, will yield a diverse library of compounds containing a known bioactive portion and a novelnatural product moiety. This approach will facilitate the identification of dual-function compounds withenhanced anti-infective properties.
This program will improve public health through the identification of the next generation of antimicrobialtherapeutic agents; particularly focusing on more effective and long-lifetime treatments for drug resistantinfections. To achieve this goal; we will develop and apply technologies for the discovery of drug leads fromnature's vast reservoir of antibacterial natural products from plants and microorganisms.
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