Viewpoint Cite This: ACS Infect. Dis. XXXX, XXX, XXX−XXX
pubs.acs.org/journal/aidcbc
Shared Platform for Antibiotic Research and Knowledge: A Collaborative Tool to SPARK Antibiotic Discovery Joe Thomas,† Marc Navre,‡ Aileen Rubio,§ and Allan Coukell*,† †
The Pew Charitable Trusts, 901 E Street NW, Washington, D.C. 20004, United States Wemberly Scientific, Inc., 1025 Alameda de las Pulgas, #116, Belmont, California 94002, United States § Spero Therapeutics, 675 Massachusetts Avenue, 14th Floor, Cambridge, Massachusetts 02139, United States
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ABSTRACT: The discovery of urgently needed antibiotics is hindered by challenges to information sharing. To help address this challenge, The Pew Charitable Trusts launched SPARK: the Shared Platform for Antibiotic Research and Knowledge. SPARK is an online, publicly available, interactive database designed to help scientists build on previous research and generate new insights to advance the field’s understanding of Gram-negative permeability. This Viewpoint details how data are selected and integrated into the platform, how scientists can use SPARK to share their data, and the ways the scientific community can access and use these data to develop hypotheses. companies, SPARK provides a “virtual lab” environment, replicating the institutional knowledge, interdisciplinary knowledge sharing, and scientific economies of scale previously found in large research and development teams.
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hile the global threat of antibiotic resistance continues to grow, the pipeline of novel antibiotic candidates to treat highly resistant infections remains thin. In 2016, The Pew Charitable Trusts’ Scientific Roadmap for Antibiotic Discovery1 synthesized input from a multidisciplinary group of scientific experts and identified a need to (1) Understand and overcome barriers for drugs targeting Gram-negative bacteria in order to generate and tailor new chemical matter for antibiotic discovery (2) Create a framework to efficiently share information, expertise, and materials across the research community To address these priorities, Pew built SPARK: the Shared Platform for Antibiotic Research and Knowledge. SPARK is a publicly accessible, interactive, online platform designed to facilitate scientific collaboration and accelerate antibiotic discovery. SPARK utilizes technology developed by Collaborative Drug Discovery, Inc. and features built-in software for multiparameter search, data visualization, computational modeling, and conversation. SPARK licenses are available at no cost to users; for more information, visit pewtrusts.org/ spark-antibiotic-discovery to learn more about how to obtain a free license to access SPARK.
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SCIENTIFIC GOALS AND DATA SCOPE The data housed on SPARK are collected with a focus on helping to further scientific understanding of the properties that allow molecules to enter and stay inside Gram-negative bacteria. These organisms are distinguished by a pair of membranes with orthogonal characteristics and a wide variety of efflux pumps, making them particularly difficult to kill. Gram-negative bacteria are responsible for a growing number of highly resistant infections. Although the physicochemical properties of Gram-negative antibiotics are observably different from those of other drugs, researchers’ general lack of understanding of how molecules enter Gram-negative bacteria hinders rational drug design.2−4 Furthermore, although new, innovative methods are emerging, the lack of a validated high-throughput assay to measure compound accumulation in Gram-negative bacteria independent of antibacterial activity presents a major barrier toward identification of novel chemical matter with appropriate properties for Gram-negative permeation. To support the development of a gold-standard assay, SPARK collects data from studies that employed a wide variety of different methods to infer or directly measure accumulation. Some studies compare bioactivity in hyper- or hyposensitive mutants with engineered permeability or efflux properties.5−7 Others explore situations in which compounds exhibit similar potency when exposed directly to the target but varied wholecell killing activity.8 Recently, innovative studies have emerged that leverage mass spectrometry to directly measure levels of compound accumulation in bacterial cells. As these studies address issues around validation of subcellular localization,
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SPARK: THE SHARED PLATFORM FOR ANTIBIOTIC RESEARCH AND KNOWLEDGE As companies and investors continue to shift away from antibiotic research and development, decades of antibiotic discovery knowledge and expertise are at risk of being lost. Antibiotic discovery findings are currently scattered across academic literature or are never published at all, making it difficult for scientists to build upon previous work. Additionally, scientists face practical hurdles in communicating findings to the wider community in real time. Without a mechanism to share both historical data and current insights, past lessons learned are lost, and often, the same mistakes are repeated. SPARK collects and organizes antibiotic discovery data to make it easily accessible to the scientific community. As the antibiotic discovery landscape shifts to smaller laboratories and © XXXX American Chemical Society
Received: August 1, 2018
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DOI: 10.1021/acsinfecdis.8b00193 ACS Infect. Dis. XXXX, XXX, XXX−XXX
ACS Infectious Diseases
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Figure 1. How data sets are optimized in SPARK. Reprinted by permission of The Pew Charitable Trusts.
data uploads according to the standards process outlined below. The timing of public release will be dictated by donors. To obtain a more complete picture of the universe of data that could be relevant to SPARK, the authors and Discovery Experts are also conducting an ongoing landscape analysis consisting of literature reviews and semistructured interviews with academic and industry scientists. This analysis has already revealed many of the technical and legal barriers to sharing unpublished data and will inform the platform’s ongoing data acquisition strategy. As promising unpublished data sets are identified, they will be included according to their scientific value and the feasibility of incorporation. Scientific value will be determined in the context of SPARK’s primary goal of furthering understanding of Gram-negative accumulation, while also balancing the need to incorporate chemical diversity in the database.
testing across Gram negative species, and improvement in throughput, it appears that one or more routine, higher throughput, activity independent accumulation assays may be readily available for testing across multiple chemical scaffolds.9,10 By incorporating data from a wide variety of studies, SPARK could help disseminate new technological advances throughout the community, allow researchers to quantitatively compare the results of different methodologies, and drive hypothesis generation and thus new experiments to better assess and validate emerging approaches.
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DATA SOURCES: PUBLISHED, UNPUBLISHED, AND VISION FOR GROWTH SPARK aims to house data from both published and unpublished sources. The initial pool of published literature data was compiled on the basis of input from the SPARK Discovery Experts. Likewise, the unpublished data sets included on the platform were voluntarily donated for purposes of public use. Moving forward, SPARK will serve as a resource for sharing new findings ahead of publication, previously unpublished data from past academic or industry efforts, and published literature data. SPARK could also serve as a repository for data generated by global research and development initiatives, such as those supported by CARB-X, NIAID, GARDP, IMI, JPIAMR, and LifeArc. SPARK users can share their own data or suggest literature sources for inclusion by contacting
[email protected]. SPARK team members will work with data donors to facilitate
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DATA STANDARDS AND CURATION SPARK’s data standards and curation rules, developed by the Discovery Experts using a consensus approach, are designed to allow a minimal barrier to entry for inclusion of diverse types of information while minimizing noise from irrelevant and lowquality data. The two-stage process, depicted in Figure 1, begins by ensuring that the data entered are relevant to SPARK’s scientific goals and that all relevant data and meta-data are captured. Data submitters are encouraged to include information on compound structure, defined target or pathway identifier, organism (including species and strain identifier), and accompanying measurement (number). Additional fields B
DOI: 10.1021/acsinfecdis.8b00193 ACS Infect. Dis. XXXX, XXX, XXX−XXX
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utilizing a controlled vocabulary will be available to capture additional relevant information, such as assay conditions, that characterizes the data in a consistent way that is easily searchable and usable. Following this validation, uploaded data will be posted publicly to SPARK and organized by the data source. Following this first stage of data standardization, curators will assess the integrity and quality of the uploaded data sets using publicly posted criteria. In the second stage, curators transform the data into tables organized by assay type, for example, minimum inhibitory concentration (MIC). This creates unified, bridged sources with data from studies across decades of published literature and, in the future, unpublished investigations from academia, industry, and nonprofit organizations. These curated data sets provide the community with unique and high-value resources affording users not only timely access to individual data sources but also the ability to confidently search and identify trends across a wide diversity of studies.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Allan Coukell: 0000-0002-8438-9214 Notes
Neither the SPARK Discovery Experts nor their organizations necessarily endorse the conclusions provided in this Viewpoint. The authors declare the following competing financial interest(s): M.N. is a consultant for Collaborative Drug Discovery, Inc. and Facile Therapeutics. A.R. is an employee of Spero Therapeutics.
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ACKNOWLEDGMENTS The Pew Charitable Trusts would like to thank the SPARK Discovery Experts for helping to guide the development of every aspect of the platform, from data scope to usability. The SPARK Discovery Experts are Aileen Rubio (Spero Therapeutics), Alice Erwin (Erwin Consulting), Andy Merritt (LifeArc), Brad Sherborne (Merck & Co. Inc.), Cheryl Quinn (QnA Pharma Consulting), David Swinney (iRND3), Helen Zgurskaya (University of Oklahoma), Johannes Zuegg (COADD), Lynn Silver (LL Silver Consulting), Marc Navre (Wemberly Scientific), Marshall Morningstar (Broad Institute), Paul Hergenrother (University of Illinois at Urbana− Champaign), Richard Lee (St. Jude Children’s Research Hospital), and Andrew Tomaras (BacterioScan Inc.).
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HOW SCIENTISTS COULD USE SPARK TO ACCELERATE DISCOVERY By organizing data from past and current efforts, SPARK gives users unprecedented access to antibiotic discovery knowledge and the ability to identify critical gaps in the field’s knowledge of Gram-negative permeability. The growing compilation of data, combined with SPARK’s search, visualization, and modeling tools, should provide scientists with the tools to identify patterns to inform rational design of future molecules that may successfully penetrate Gram-negative bacteria and evade efflux. As technologies to measure compound accumulation in Gram-negative bacteria continue to advance, SPARK offers users the opportunity to share findings and generate hypotheses about the properties of molecules that favor greater accumulation. For example, a computational model trained on compounds known to accumulate could be utilized to sort through previously untested molecules and prioritize scaffolds for further testing. A recent study by Richter and colleagues9 suggests that this approach could show promise. By providing access to a wider range of data and easy-to-use model building tools, SPARK could democratize this strategy. Using SPARK, the authors developed several proof-of-concept machine-learning models that all users can access and utilize. Scientists may leverage SPARK’s data and software tools to generate physicochemical guidelines for Gram-negative entry based on chemical class, target, entry route, bacterial species, or other parameters. After these guidelines are refined through iterative hypothesis testing, they could be used to inform the construction of small-molecule libraries tailored for antibiotic discovery. These libraries could provide discovery scientists with a deeper pool of promising chemical matter to draw from in their search for the next antibiotic.
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REFERENCES
(1) The Pew Charitable Trusts. (2016) A Scientific Roadmap for Antibiotic Discovery, http://www.pewtrusts.org/en/research-andanalysis/reports/2016/05/a-scientific-roadmap-for-antibioticdiscovery. (2) O’Shea, R., and Moser, H. E. (2008) Physicochemical properties of antibacterial compounds: implications for drug discovery. J. Med. Chem. 51 (10), 2871−2878. (3) Payne, D. J., Gwynn, M. N., Holmes, D. J., and Pompliano, D. L. (2007) Drugs for bad bugs: confronting the challenges of antibacterial discovery. Nat. Rev. Drug Discovery 6 (1), 29−40. (4) Tommasi, R., Brown, D. G., Walkup, G. K., Manchester, J. I., and Miller, A. A. (2015) ESKAPEing the labyrinth of antibacterial discovery. Nat. Rev. Drug Discovery 14 (8), 529−542. (5) Krishnamoorthy, G., Leus, I. V., Weeks, J. W., Wolloscheck, D., Rybenkov, V. V., and Zgurskaya, H. I. (2017) Synergy between Active Efflux and Outer Membrane Diffusion Defines Rules of Antibiotic Permeation into Gram-Negative Bacteria. mBio 8 (5), e01172-17. (6) Iyer, R., Sylvester, M. A., Velez-Vega, C., Tommasi, R., DurandReville, T. F., and Miller, A. A. (2017) Whole-cell-based assay to evaluate structure permeation relationships for carbapenem passage through the Pseudomonas aeruginosa porin OprD. ACS Infect. Dis. 3 (4), 310−319. (7) Isabella, V. M., Campbell, A. J., Manchester, J., Sylvester, M., Nayar, A. S., Ferguson, K. E., Tommasi, R., and Miller, A. A. (2015) Toward the rational design of carbapenem uptake in Pseudomonas aeruginosa. Chem. Biol. 22 (4), 535−547. (8) Brown, M. F., Reilly, U., Abramite, J. A., Arcari, J. T., Oliver, R., Barham, R. A., Che, Y., et al. (2012) Potent inhibitors of LpxC for the treatment of Gram-negative infections. J. Med. Chem. 55 (2), 914− 923. (9) Richter, M. F., Drown, B. S., Riley, A. P., Garcia, A., Shirai, T., Svec, R. L., and Hergenrother, P. J. (2017) Predictive compound accumulation rules yield a broad-spectrum antibiotic. Nature 545 (7654), 299−304. (10) Tian, H., Six, D. A., Krucker, T., Leeds, J. A., and Winograd, N. (2017) Subcellular chemical imaging of antibiotics in single bacteria
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CONCLUSION Revitalizing antibiotic discovery is essential to respond to current and future threats. No single group has all the answers needed to overcome the scientific roadblocks hindering discovery, but by organizing the field’s knowledge and working collaboratively, these challenges could be surmounted together. The authors invite you to grow and shape SPARK into a valuable resource for sparking antibiotic discovery. C
DOI: 10.1021/acsinfecdis.8b00193 ACS Infect. Dis. XXXX, XXX, XXX−XXX
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using C60-secondary ion mass spectrometry. Anal. Chem. 89 (9), 5050−5057.
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DOI: 10.1021/acsinfecdis.8b00193 ACS Infect. Dis. XXXX, XXX, XXX−XXX
