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Exploiting Microbiome and Synthetic Biology to Discover and Produce Naturally Occurring Antibiotics


The explosion in the “omics” field has allowed for unprecedented genetic identification of some of the billions of bacteria that comprise the world of the microbiome. A potential wealth of information is available through the study of species that have developed sophisticated defense mechanisms to protect themselves from the onslaught of foreign invaders. Recent examples include the microbiome of the new world vulture and in humans. The potential for identification of natural product antibiotics is now within technical reach, and could represent a large family of hitherto unknown naturally occurring antibacterial agents. Furthermore, current data suggest that these natural products are produced from a cluster of genes, and likely represent a variety of agents that have singular and synergistic effects against invading bacteria. Isolation of the natural products, as well as elucidation of the genes involved in their biosynthesis, might provide a number of convergent paths towards the development of new and improved antibacterial therapeutic agents. Another advantage of these types of investigations is the well-established regulatory pathway to FDA approval. The ever-increasing discovery of drug resistant strains, such as methicillin resistant Staphylococcus aureus (MRSA), coupled with the dwindling antibiotic research efforts in pharmaceutical companies, is one reason that Executive Order 13676 was issued in September 2014 to expedite the discovery and development of new antibacterial agents. The Department of Defense (DoD) is increasingly concerned with both multi-drug resistant strains of bacteria, as well as those bacterial threats that could potentially be used as biowarfare agents. In an effort to address these gaps, the DoD is soliciting researchers who will take advantage of recent advances in technology to identify and develop new families of antibiotics derived from the microbiome. PHASE I: Perform proof-of-concept studies to define the source of the microbiome, the identity of a gene cluster relating to the biosynthesis of antibacterial agents, and in vitro data showing antibacterial effect. It is not expected at this stage that any natural products will be isolated and identified, rather that crude mixtures would be tested to show in vitro activity. The bacterium does not, at this stage, need to be a priority for the DoD, and could be Escherichia coli, Klebsiella pneumonia, Acinetobacter baumannii, Pseudomonas aeruginosa, etc. If selected for a Phase II contract, the Phase I Option period should be used to test the crude mixtures of natural products against bacteria of interest to the DoD (Bacillus anthracis, Burkholderia mallei, Burkholderia pseudomallei, Francisella tularensis, and Yersinia pestis). The government currently offers a Core testing capability to perform in vitro and/or in vivo screening of compounds (lead, advanced, or licensed) alone or in combination against an extensive panel of biodefense pathogens, as well as a panel of multi-drug resistant (MDR) pathogens, to generate minimum inhibitory concentration (MIC) data at no cost, and with no intellectual property implications to the providing party. Offerors selected for Phase I award will be provided additional information regarding these opportunities. PHASE II: During Phase II, it is expected the crude mixtures used in Phase I will be purified to homogeneity. Novel chemical entities will be fully defined and characterized. These materials will be further tested for efficacy in in vitro assays. Depending on the complexity of the structure, it may be advantageous to develop a medicinal chemistry program around any novel chemotype discovered. Mechanism of action studies should be commenced to understand the target(s) of these natural products in order to further exploit the compounds as potential therapeutics. It is further anticipated that the cluster of genes responsible for the biosynthesis of these small molecule compounds will be fully identified, and methods for their expression in suitable vectors will be developed. Synthetic biology approaches to constructing bio-factories for the large scale production of these materials could be explored for feasibility. Structure-function and/or structure-activity relationships should be established during this Phase, and the further development of these novel compounds as novel antibacterial agents defined. These studies would encompass a large spectrum of bacterial targets, and identification of broad-spectrum agents should be a priority. By studying and understanding the mechanism of action of these compounds, it may be advantageous to define a multi-pronged therapeutic regime similar to what could be found in nature. The primary deliverable from this Phase of the project will be to demonstrate in vivo efficacy (target >50% survival in a lethal challenge model when initially dosed greater than or equal to 12h post-exposure) of one or more of these compounds against multiple bacteria, including but not limited to agents of interest to the DoD (B. anthracis, B. mallei, B. pseudomallei, F. tularensis, and Y. pestis). Ideally, these compounds will show characteristics amenable to advancement into pre-clinical and clinical studies. PHASE III: Phase III activities will focus on advancing the most promising candidate(s) towards the clinic and FDA approval. This would include pre-clinical studies such as further animal efficacy studies, pharmacology, toxicology, formulation, and dose ranging studies to determine likely human dosing, routes of administration, as well as manufacturing and all requisite studies to file an Investigational New Drug (IND) application with the FDA. PHASE III DUAL USE APPLICATIONS: Although the DoD has specific requirements for therapeutics and/or prophylaxis against bacterial agents that can be used as biowarfare agents, it is fully expected that any product derived from this work will have significant and broad commercial applications to the health and safety of the general public.


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