Rapid Therapeutic Development Pipeline

The Seeker requires an achievable strategy for evolving species-specific therapies for unknown bacterial isolates within as little as seven days after receiving a culturable sample.

This is an Ideation Challenge so your creativity and experience qualify you to participate in this challenge. Responses are expected to be about 2-3 written pages not including figures, however there is no strict limit on length.

Detailed Description & Requirements

Background & Impact Statement

Background

Bacteria have demonstrated a tenacious ability to evolve resistance to key therapeutic compounds, especially in clinical settings where pathogens and therapeutics frequently come in contact [1]. Consequently, the finite array of safe and effective antibacterial therapies is being gradually eroded by the persistent emergence of drug-resistant bacteria. One result of bacterial-acquired antibiotic resistance has been that the annual United States mortality from multi-drug resistant Staphylococcus aureus infections now exceeds AIDS-related deaths [2].

Bacterial adaptation to antimicrobial compounds is driven by an array of genetic phenomena that include localized mutations, genetic recombination events, and the exchange of mobile genetic elements [3-5]. However, prokaryotic, eukaryotic, and viral organisms, which naturally compete with bacterial pathogens in shared environments, rely on similar mechanisms to maintain a competitive edge. Examples most notably include other bacteria, which produce compounds to limit competition and predation [6, 7], phage, which evolve species-specific strategies for invading and propagating within bacteria [5, 8], and members of the host’s adaptive immune system, which are rapidly enriched for their abilities to target pathogens.

Remarkably, the host’s adaptive immune response can require as little as seven days to screen and enrich leukocytes that are capable of producing pathogen specific antibodies without, in most cases, adversely affecting the host. Antibody affinity for specific pathogens further increases during subsequent exposures via isotype switching and somatic hypermutation, genetic processes that contribute to antibody affinity maturation.

The Seeker is looking for novel laboratory-based mutagenesis and selection processes that qualitatively match the speed and specificity of the adaptive immune response to unknown bacterial pathogens. Winning solutions will describe a novel therapeutic discovery pipeline that can be developed and implemented by the Seeker to rapidly evolve ostensibly safe and effective therapeutic candidates for novel bacterial pathogens in as little as seven days, although longer discovery processes will also be considered. Extensive in vivo safety and efficacy studies are not part of the therapeutic discovery pipeline described in this challenge and need not be addressed by the Solver.

The Challenge
The Seeker requires an achievable strategy for evolving species-specific therapies for unknown bacterial isolates within as little as seven days after receiving a culturable sample. If the target of 7 days is not achievable, longer discovery processes will also be considered.

Technical Requirements
All Proposals will be solely on the strengths of the theoretical proposal. While it is important for the Solver to demonstrate a technically solid approach via references to published studies, no independent experimentation is required from the Solver. Proposals will be scored on their ability to meet the six technical requirements listed below. The solution with the highest score will be granted at least $5000. The remaining $5000 will be divided among leading contenders at the Seeker's discretion.

• Speed. The solutions will be rated on the speed with which the proposed development pipeline is expected to produce an animal-testable bacterial therapeutic after receiving a culturable unknown. Although challenge targets a seven-day discovery cycle, solutions describing longer processes will also be considered and could also be awarded.
• Specificity. Solutions will be rated on their projected ability to generate therapeutics that narrowly target an unknown bacterial species, much as the adaptive immune system rapidly targets specific pathogens.
• Versatility. While the Seeker realizes that the same strategy may not be applicable to all potential bacterial pathogens, Solvers that successfully argue for the broad applicability of their strategy will receive a higher score.
• Safety. The Seeker will favor strategies that are reasonably expected to generate safe and effective therapeutics when administered to infected hosts in a manner proposed by the Solver.
• Feasibility. The Seeker is looking for a solution that can likely be validated within a reasonable time and budget. Therefore solutions that propose a finite series and realistic steps to implementation will be scored higher.
• Novelty. The Seeker is looking for solutions that differ from those already explored in scientific and medical literature and will rate innovative solutions higher than those that describe existing strategies.

References

1. Fischbach, M.A. and C.T. Walsh, Antibiotics for emerging pathogens. Science, 2009. 325(5944): p. 1089-93.
2. Klevens, R.M., et al., Invasive methicillin-resistant Staphylococcus aureus infections in the United States. JAMA, 2007. 298(15): p. 1763-71.
3. Schaefler, S., Bacteriophage-mediated acquisition of antibiotic resistance by Staphylococcus aureus type 88. Antimicrob Agents Chemother, 1982. 21(3): p. 460-7.
4. Brussow, H., C. Canchaya, and W.D. Hardt, Phages and the evolution of bacterial pathogens: from genomic rearrangements to lysogenic conversion. Microbiol Mol Biol Rev, 2004. 68(3): p. 560-602.
5. Nakagawa, I., et al., Genome sequence of an M3 strain of Streptococcus pyogenes reveals a large-scale genomic rearrangement in invasive strains and new insights into phage evolution. Genome Res, 2003. 13(6A): p. 1042-55.
6. Slechta, E.S. and M.A. Mulvey, Contact-dependent inhibition: bacterial brakes and secret handshakes. Trends Microbiol, 2006. 14(2): p. 58-60.
7. Hale, C.R., et al., RNA-guided RNA cleavage by a CRISPR RNA-Cas protein complex. Cell, 2009. 139(5): p. 945-56.
8. Papke, R.T. and W.F. Doolittle, Phage evolution: new worlds of genomic diversity. Curr Biol, 2003. 13(15): p. R606-7.

Project Criteria

The Seeker requires an achievable strategy for evolving species-specific therapies for unknown bacterial isolates within as few as seven days of obtaining a culturable sample. Since solutions will be ranked solely on their theoretical merit, your proposal should include the following information:

• Detailed description of a concept or that can meet the Technical Requirements as described above.
• Referenced explanations as to why you believe that your concept meets the requirements listed in the detailed description.
• As much existing data as possible to support the feasibility of your concepts.

Your proposal should not include:

• Personal identifying information (name, username, address, phone, email, personal website, resume, etc.)
• Intellectual Property you do not wish to make public.

After the submission deadline, the Seeker will evaluate all submissions based on the technical criteria described above and identify the best proposal(s) for the award(s). The Seeker will not provide technical feedback for proposals that are not selected. You will be notified of the outcome of your submission.

• There is a guaranteed award. The award will be paid to the best submissions, which are solely determined by the Seeker. The total payout will be $10,000. The Seeker can payout as one award or split it among the best submissions. One award will be at least $5,000 and no award will be less than $1,000.