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At least 19 records
All sourcesNASA NTRSDOE OSTI
DOE OSTI2024

Repurposing Inactive Oil and Gas Wells for Energy Storage: Maximizing the Potential Via Optimal Drivetrain Control: Preprint

In recent years, there has been a growing emphasis on utilizing energy storage to enhance grid resilience against disruptive events. While renewable energy supply continues to expand, gravity-based solutions like pumped hydro remain dominant in the commercial space. However, their geographical limitations constrain availability, scalability, and increase costs for co-locating solar and wind energy. An alternative approach proposes repurposing idle oil and gas wells located closer to existing grid infrastructure, offering a promising and cost-effective solution. This paper addresses the optimization and control of a regenerative drive system coupled to an interior permanent magnet synchronous machine in a 300-meter well with a 100-Newton weight. The study employs a dynamic MATLAB/Simulink model to simulate the operation of the electric drivetrain system during storage and discharge operations. The results demonstrate an initial round-trip efficiency of 85.9% for the electrical system alone and identify crucial factors for maximizing efficiency. The optimized operation and control of the electromechanical drivetrain system hold great potential for minimizing the levelized cost of storage while maximizing efficiency and revenue generation.

ENERGY STORAGE,ENGINEERING↗
DOE OSTI2023

Wind Turbine Blade Repurposing and Recycling: Coupling Repurposing Methods with 3D Printing Technology

Fiber-reinforced thermoplastic composites continue to be implemented in several marketsbecause of their strength capacity and light weight. Especially in the wind industry, wind bladesare made of this material which makes them ideal for wind energy generation, but bladesbecome a problem at end-of-life. Because recycling thermoplastic composites technologiesare still not cost and environmentally effective, research in this space is needed. This paperpresents a case study for coupling repurposed wind turbine blades and 3D printing technology.The purpose is to remanufacture decommissioned wind blades into bus stop roof and seatingsections to then use recycled glass fiber from a decommissioned wind turbine blade to 3Dprint structural and/or fixtures needed in the assembly. We provide an overview of the designprocess, and the development process steps in repurposing and 3D printing the material,delving into key parameters required for a successful implementation.

Henao, Yulizza↗
DOE OSTI2022

Repurposing Fossil-Fueled Assets For Energy Storage

The annual retirement of U.S. coal-fired electricity generation units (CF-EGU) is at an all-time high and is expected to continue. This loss of reliable baseload generation, combined with predicted growth of variable renewable energy (VRE) generation, is expected to stress grid reliability as the number of load-following resources drops below the experienced load variability. Many regions are already experiencing challenges, and fossil retirement-related warnings by the North American Electric Reliability Corp. are becoming more dire. All CF-EGU retirements pose significant challenges to asset owners, local workforces, and their communities. Repurposing a retiring CF-EGU as a long-duration energy storage plant can address these challenges and offer a suite of additional benefits to asset owners, the grid, and society. This project performed a techno-economic evaluation and assessment of repurposing a Duke Energy fossil-fueled asset (in particular, a coal plant) into an energy storage system by integrating the retiring asset with a Malta long duration Pumped Heat Energy Storage (PHES) system. The project validated the technoeconomic benefits of repurposing retiring coal plants into long-duration energy storage using Malta’s PHES. Key findings for this project are summarized below: (1) Technical: (a) Retiring coal plants (and other steam turbine fossil generation) can be repurposed to enable the clean energy transition using Malta’s technology. (b) For older retiring coal plants, repurposing the site and electrical interconnection for a standalone PHES plant is the most economically favorable option. (c) For newer coal plants where there is also a local peaking capacity need, repowering the steam cycle into a hybrid integration with PHES is attractive. (d) A process was developed to assist fossil generation owners in choosing the best path for each plant’s circumstances. (2) Economic (a) Communities facing economic challenges caused by the retirement of fossil generation would benefit from repurposing the plant as long-duration energy storage using Malta’s PHES. (b) On a $/MW basis, repowering retiring coal units into Malta PHES plants can maintain the same number and types of jobs and economic activity. (c) For a 70% carbon reduction scenario, a 10-hour Malta PHES plant is more economic for the asset owner than similar-power 4-hour batteries. This project showed that repurposing a retiring coal unit into thermal energy storage, by integrating it with a Malta PHES system, makes techno-economic sense. At least two integration options are available, with the optimal solution depending on the coal plant and its location. Repurposing retiring coal plant into energy storage results in economic benefits for the plant owner and local communities.

20 FOSSIL-FUELED POWER PLANTS↗
DOE OSTI2024

Life Cycle Assessment and Life Cycle Cost Analysis of Repurposing Decommissioned Wind Turbine Blades as High-Voltage Transmission Poles

Wind energy is widely deployed and will likely grow in service of reducing the world’s dependency on fossil fuels. The first generation of wind turbines are now coming to the end of their service lives, and there are limited options for the reuse or recycling of the composite materials they are made of. Current literature has verified that there is no existing recycling pathway (i.e., mechanical, chemical, thermal methods of recovery, etc.) for end-of-life materials in wind blades that can meet cost parity with landfilling in the US. However, to the authors’ knowledge there is no study to date that uncovers the cost structures associated with repurposing wind turbine blades in the US. Repurposing could offer a cost-competitive advantage through displacement of higher-value products, rather than materials or chemical constituents alone. This study implements life cycle assessment (LCA) and life cycle cost analysis (LCC) to assess the environmental and financial implications at each stage of repurposing wind turbine blades as the primary load-carrying elements for high-voltage transmission line structures in the United States. This case study contribution to knowledge is based on the successful management of construction waste by analyzing an application for repurposing construction demolition waste. Specifically, this study presents an environmental and financial analysis of repurposing wind turbine blades as transmission line poles. Under this case study, our results show that BladePoles have lower greenhouse gas emissions than steel poles, and we anticipate BladePoles will be less costly than steel poles. Overall emissions are most sensitive to combustion emissions, driven primarily by transportation distance and hours of required crane operations during the installation process. Compared to other evaluated recycling methods, repurposing wind blades as BladePoles has the least overall global warming potential.

42 ENGINEERING↗
DOE OSTI2023

Developing a SARS-CoV-2 main protease binding prediction random forest model for drug repurposing for COVID-19 treatment

The coronavirus disease 2019 (COVID-19) global pandemic resulted in millions of people becoming infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus and close to seven million deaths worldwide. It is essential to further explore and design effective COVID-19 treatment drugs that target the main protease of SARS-CoV-2, a major target for COVID-19 drugs. In this study, machine learning was applied for predicting the SARS-CoV-2 main protease binding of Food and Drug Administration (FDA)-approved drugs to assist in the identification of potential repurposing candidates for COVID-19 treatment. Ligands bound to the SARS-CoV-2 main protease in the Protein Data Bank and compounds experimentally tested in SARS-CoV-2 main protease binding assays in the literature were curated. These chemicals were divided into training (516 chemicals) and testing (360 chemicals) data sets. To identify SARS-CoV-2 main protease binders as potential candidates for repurposing to treat COVID-19, 1188 FDA-approved drugs from the Liver Toxicity Knowledge Base were obtained. A random forest algorithm was used for constructing predictive models based on molecular descriptors calculated using Mold2 software. Model performance was evaluated using 100 iterations of fivefold cross-validations which resulted in 78.8% balanced accuracy. The random forest model that was constructed from the whole training dataset was used to predict SARS-CoV-2 main protease binding on the testing set and the FDA-approved drugs. Model applicability domain and prediction confidence on drugs predicted as the main protease binders discovered 10 FDA-approved drugs as potential candidates for repurposing to treat COVID-19. Our results demonstrate that machine learning is an efficient method for drug repurposing and, thus, may accelerate drug development targeting SARS-CoV-2.

Research & Experimental Medicine↗
DOE OSTI2021

Near-physiological-temperature serial crystallography reveals conformations of SARS-CoV-2 main protease active site for improved drug repurposing

The COVID-19 pandemic has resulted in 198 million reported infections and more than 4 million deaths as of July 2021 (covid19.who.int). Research to identify effective therapies for COVID-19 includes: (1) designing a vaccine as future protection; (2) de novo drug discovery; and (3) identifying existing drugs to repurpose them as effective and immediate treatments. To assist in drug repurposing and design, we determine two apo structures of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease at ambient temperature by serial femtosecond X-ray crystallography. We employ detailed molecular simulations of selected known main protease inhibitors with the structures and compare binding modes and energies. The combined structural and molecular modeling studies not only reveal the dynamics of small molecules targeting the main protease but also provide invaluable opportunities for drug repurposing and structure-based drug design strategies against SARS-CoV-2.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

Repurposing Offshore Infrastructure for Clean Energy (ROICE) vs. Decommissioning – Commercial Considerations

Abstract The Repurposing Offshore Infrastructure for Clean Energy (ROICE) Program, a collaboration of the energy industry and University of Houston, proposes extending the life of up to 1,500 oil and gas platforms in the Outer Continental Shelf of the Gulf of Mexico, USA. Rather than decommissioning or converting them to underwater reefs at the end of their oil and gas production phase, the platforms could be transformed for 10–20+ years of renewable energy development, such as green hydrogen production or carbon dioxide injection and storage, resulting in significant economic, environmental, and social benefits. ROICE has already published papers on the technical and regulatory considerations for such repurposing projects. This paper focuses on the commercial considerations needed to ensure ROICE projects are economically viable and sustainable for all involved. There are potentially many entities that can come together to progress a repurposing project, including oil and gas asset owners, operators, investors, developers, contractors, manufacturers, and regulators. This paper looks at possible combinations of these entities in a ROICE project team and the various commercial agreements that will be needed to ensure a mutually successful outcome. The paper proposes adapting existing industry agreements and templates to suit, including asset transfer agreements (ATA), asset purchase agreements (APA) and joint purchasing agreements (JOA). An ATA or APA can be drafted to address the obligations and issues involved in the sale or transfer of an existing oil and gas facility to the developer, operator, non-operating interests, and financial investors in a ROICE project, while a JOA can be drafted to govern the rights, obligations, and financial requirements of the parties involved in the development and operation.

Legge, G. [Endeavor Management, USA]↗
DOE OSTI2020

Repurposing Hanford Waste Tank AP-106 for Interim Storage of Treated Low-Activity Waste - 20044

Hanford Double-Shell Tank AP-106 is being repurposed to serve as the lag storage tank holding feed for the Direct Feed Low-Activity Waste (DFLAW) process at the Waste Treatment and Immobilization Plant (WTP). The repurposing process is the sequence of tank additions and transfers that will remove the Cs 137 inventory from AP-106. The repurposing process steps are designed to remove Cs-137 more effectively and efficiently as compared to regular supernatant transfers. The process steps are estimated to take 2-months to complete. (authors)

12 MANAGEMENT OF RADIOACTIVE AND NON-RADIOACTIVE W↗
DOE OSTI2025

Hydrogen-Battery Hybrid Energy System on Repurposed Offshore Platforms for Efficient Clean-Energy Transition

Due to the rising global energy demand and enhanced awareness of the environmental impact of fossil fuels, the Gulf of Mexico, traditionally known for oil extraction, offers a distinct chance to repurpose the existing offshore infrastructure. With the depletion of oil reserves, it is feasible to adapt previously utilized floating platforms for extraction to generate renewable energy, specifically through wind-generated power and hydrogen production. This adaptation seeks to promote a transport system that is more ecologically friendly in the future. Offshore wind turbines serve as the main energy source, with help from battery storage and hydrogen production to enhance the overall system performance, hydrogen creation, fuel, and electricity delivery for sustainable energy production. The system is divided into two distinct cases, each evaluated for cost, performance, and feasibility, with a focus on minimizing both the Levelized Cost of Energy (LCOE) and the Levelized Cost of Hydrogen (LCOH). The first case examines the integration of offshore wind turbines with hydrogen production. Excess electricity generated by wind turbines is directed toward hydrogen production via electrolysis. The hydrogen produced can be used as fuel for vehicles or transported to the shore via pipelines. The second case investigates a technology that combines wind turbines with battery storage. The batteries possess an ability to supply electricity for a continuous duration of 4 hours maximum each day. The main objective is to reduce the LCOE by considering the battery's charging and discharging cycles, together with the uncertain attributes of wind power and battery deterioration. The produced energy can be distributed for onshore applications or utilized for the purpose of offsetting offshore loads such as subsea oil and gas production, transportation, etc. The offshore hydrogen-battery hybrid system is improved via three advanced algorithms, Particle Swarm Optimization (PSO), and Grey Wolf Optimizer (GWO). In Case 1, PSO improves hydrogen production by efficiently managing the electrolyzer’s power consumption, decreasing production costs significantly. Particle Swarm Optimization (PSO) is applied to improve the efficiency of the electrolyzer, reducing production costs and achieving an optimized CAPEX of $240.00 million (from an initial $300.00 million) and OPEX of $9.60 million per year. This system produces 4,720,000 kg of hydrogen annually, with a Levelized Cost of Hydrogen (LCOH) of $6.40/kg and an annual profit of $9.27 million. In Case 2, GWO effectively reduces the overall energy cost by improving the charge-discharge management of batteries, which extends battery life and optimizes their use. The second case focuses on integrating battery storage, optimized using the Grey Wolf Optimizer (GWO), which enhances battery charge-discharge cycles, extending battery life and lowering costs. This system achieves an optimized CAPEX of $204.80 million (from an initial $256.00 million) and OPEX of $9.29 million per year, producing 310883.39 MWh of electricity annually at a Levelized Cost of Energy (LCOE) of $86.13/MWh, with an annual profit of $6.25 million. The implementation of a comprehensive strategy results in a substantial reduction in costs, improved energy efficiency, and a dependable supply of both electric power and hydrogen, emphasizing the benefits of converting offshore oil platforms for clean energy transition. This study explores a clean strategy to enable cost-effective repurposing of offshore O&G platforms. Both cases highlight the economic and technical feasibility of transitioning offshore oil platforms to clean energy systems, demonstrating substantial cost reductions and reliable energy and hydrogen supplies for sustainable energy production.

32 ENERGY CONSERVATION, CONSUMPTION, AND UTILIZATI↗
DOE OSTI2025

Repurposing Post-Consumer Polyethylene to Access Cross-Linked Polyethylene with Reprocessabilty, Recyclability, and Tunable Properties

Polyethylene (PE) is the most widely produced plastic but accumulation and resistance to degradation has significantly contributed to the plastic waste crisis. Upcycling has presented promising solutions to transform PE waste into value-added products. In this study, mixed post-consumer PE was successfully repurposed into reprocessable and chemically recyclable cross-linked polyethylene (XLPE). This process involved converting PE into telechelic oligomers, followed by repolymerization using a hybrid cross-linking system consisting of a dynamic cross-linker 2,4,6-triethoxy-1,3,5-triazine (TETA) and non-dynamic cross-linker tris(6-isocyanatohexyl)isocyanurate (Tri-HDI). In the resulting XLPE, TETA facilitated iterative reprocessing with minimal property degradation across cycles, whereas Tri-HDI helped preserve functional performance throughout service life. Compared to PE, XLPE exhibited enhanced mechanical properties, reduced creep deformation under application-relevant temperatures, and high temperature structural stability. Notably, copolymerizing PE oligomers with commercial macrodiols was employed to create composite XLPEs, enabling tuning material properties. After use, XLPE can be efficiently and selectively depolymerized under mild conditions, even when mixed with commercial insulator cables. This depolymerization allows for the recovery of the constituent building blocks, enabling purification and subsequent repolymerization for reuse. This approach demonstrates the potential of repurposing plastic waste into sustainable materials and fostering the development of a circular economy.

INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMI↗
DOE OSTI2026

Identification of drug repurposing candidates for amyotrophic lateral sclerosis using electronic health records: a retrospective cohort study

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with a life expectancy of only 3–5 years and few approved treatments. To identify drug repurposing candidates for the treatment of ALS, we analysed the electronic health records (EHRs) of a large cohort of military veterans with ALS. We analysed the EHRs of individuals in the US Veterans Health Administration (VHA) database who were diagnosed with ALS between Jan 1, 2009 and Dec 31, 2019 to assess medication effects. Individuals without recorded prescriptions after the date of diagnosis were excluded. Two sets of criteria were applied to ascertain exposure. Exposure criteria A were met if the dispense date or the end date of the medication was within 12 months of ALS diagnosis and the end date was at least 6 months after the dispense date. Exposure criteria B were met if there were at least two dispenses within 6 months before diagnosis and 12 months after diagnosis. Propensity score-matched control groups were generated on the basis of confounders included in the EHR, with methodology of potential outcomes used to infer treatment effects. The primary outcome was death. A standard Cox proportional hazards analysis was done to assess association with survival. Survival was defined as the time from diagnosis date recorded in the EHR to death reported in the Department for Veterans Affairs Vital Status File. Follow-up survival time was censored on Dec 31, 2020, for those alive on this date. Downstream protein targets of drugs with clinically significant effects were analysed using the protein–protein interaction networks-based algorithm PathFX. The EHRs of 11 003 individuals with ALS in the VHA database were appropriate for analysis. 162 medications with treatment groups of 30 or more individuals were identified. Among these 162 medications, 27 were associated with statistically significant changes (≥0·1) in the hazard ratio (HR) for death. 18 of the medications were associated with a reduced HR for death (prolonged survival), and nine were associated with an increased HR for death (reduced survival). Drugs associated with reduced HR included HMG-CoA reductase inhibitors (simvastatin, pravastatin, lovastatin, and atorvastatin), PDE5 inhibitors (vardenafil and sildenafil), and α-adrenergic antagonists (tamsulosin and terazosin). The medications associated with an increased HR were drugs used either in the management of clinical features of ALS associated with poor outcomes or in end-of-life care. PathFx analysis identified a complex of proteins interacting with several of the identified drugs. To our knowledge, this analysis is the largest EHR-based study for identifying drug repurposing candidates for ALS. We identified several drugs that warrant further assessment as therapeutic options in ALS, as well as a protein network complex that might serve as a therapeutic target for ALS.

Reimer, Richard J. [Stanford Univ., CA (United Sta↗
DOE OSTI2024

Gcn2 structurally mimics and functionally repurposes the HisRS enzyme for the integrated stress response

Protein kinase Gcn2 attenuates protein synthesis in response to amino acid starvation while stimulating translation of a transcriptional activator of amino acid biosynthesis. Gcn2 activation requires a domain related to histidyl-tRNA synthetase (HisRS), the enzyme that aminoacylates tRNA His . While evidence suggests that deacylated tRNA binds the HisRS domain for kinase activation, ribosomal P-stalk proteins have been implicated as alternative activating ligands on stalled ribosomes. We report crystal structures of the HisRS domain ofChaetomium thermophilumGcn2 that reveal structural mimicry of both catalytic (CD) and anticodon-binding (ABD) domains, which in authentic HisRS bind the acceptor stem and anticodon loop of tRNA His . Elements for forming histidyl adenylate and aminoacylation are lacking, suggesting that Gcn2 HisRS was repurposed for kinase activation, consistent with mutations in the CD that dysregulate yeast Gcn2 function. Substituting conserved ABD residues well positioned to contact the anticodon loop or that form a conserved ABD–CD interface impairs Gcn2 function in starved cells. Mimicry in Gcn2 HisRS of two highly conserved structural domains for binding both ends of tRNA—each crucial for Gcn2 function—supports that deacylated tRNAs activate Gcn2 and exemplifies how a metabolic enzyme is repurposed to host new local structures and sequences that confer a novel regulatory function.

Science & Technology - Other Topics↗
DOE OSTI2020

Repurposing a microfluidic formulation device for automated DNA construction

Microfluidic applications have expanded greatly over the past decade. For the most part, however, each microfluidics platform is developed with a specific task in mind, rather than as a general-purpose device with a wide-range of functionality. Here, we show how a microfluidic system, originally developed to investigate protein phase behavior, can be modified and repurposed for another application, namely DNA construction. We added new programable controllers to direct the flow of reagents across the chip. We designed the assembly of a combinatorial Golden Gate DNA library using TeselaGen DESIGN software and used the repurposed microfluidics platform to assemble the designed library from off-chip prepared DNA assembly pieces. Further experiments verified the sequences and function of the on-chip assembled DNA constructs.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2026

Understanding Depolymerization and Repolymerization Toward Repurposing Polymer Waste Into Valuable Chemicals & Materials

The versatility of synthetic polymers has led to their continual and escalating production that has accompanied mismanagement at their end-of-life. Exploring and understanding complementary avenues to repurpose plastic waste beyond traditional mechanical recycling can unlock new opportunities in providing feedstock flexibility, securing supply chains, recovering valuable materials, and enabling new valorization paths. Chemical recycling allows for the return to monomers, tailored oligomers, and polymers, even from mixed states of post-consumer waste plastics. This review article summarizes our research team's efforts on elucidating key insights surrounding plastic depolymerization and repolymerization into valorized products. We revealed organocatalyst design rules lead to highly effective and selective deconstruction of condensation polymers. The intricacies of tailoring the reaction environment to produce products of specific lengths and desired functionalities transform low-value waste feedstocks into high-performance materials with embedded circularity. Other types of polymers, including polyolefins and polyakenamers, have also been designed and converted into valuable products. There remain opportunities for further developments such as low-energy and precision depolymerization, adoption of cutting-edge small molecule transformation to access functionalized polymer scaffolds typically inaccessible otherwise, as well as precision design and understanding through the aid of advanced tools.

Galan, Nick [ORNL]↗
DOE OSTI2024

Stereodivergent photobiocatalytic radical cyclization through the repurposing and directed evolution of fatty acid photodecarboxylases

Despite their intriguing photophysical and photochemical activities, naturally occurring photoenzymes have not yet been repurposed for new-to-nature activities. Here we engineered fatty acid photodecarboxylases (FAPs) to catalyse unnatural photoredox radical C–C bond formation by leveraging strongly oxidizing excited-state flavoquinone cofactor. Through genome mining, rational engineering and directed evolution, we developed a panel of radical photocyclases (RAPs) to facilitate decarboxylative radical cyclisation with excellent chemo-, enantio-, and diastereoselectivities. Our high-throughput experimental workflow allowed for the directed evolution of FAPs. An orthogonal set of RAPs was engineered to access all four possible stereoisomers of stereochemical dyad, affording fully diastereo- and enantiodivergent biotransformations in asymmetric radical biocatalysis. Molecular dynamics simulations show that our evolved RAPs allow near-attack conformations to be easily accessed, enabling chemoselective radical cyclisation. The development of stereoselective RAPs provides unnatural C–C bond forming activities in natural photoenzyme families, which can be used to tame the stereochemistry of free radical-mediated reactions.

Ju, Shuyun (ORCID:000000020322104X)↗
DOE OSTI2026

Techno-Economic Analysis of Repurposing Natural Gas Transmission Pipeline Networks to Accommodate Hydrogen Blends

Blending hydrogen into natural gas infrastructure could supplement natural gas supply and increase resilience for applications such as ammonia production, peaking and load-following power plants, and heating. The United States has an extensive network of natural gas pipelines, but the feasibility of employing this infrastructure to transport hydrogen is unclear. We analyze the costs associated with repurposing three distinct natural gas transmission pipelines in different locations within the United States to carry blends of hydrogen up to 100% via three different pipeline network modification methods and compare against the cost of building a new dedicated hydrogen pipeline. We conduct a sensitivity analysis on the hoop stress limit of the existing pipe, techno-economic parameters, emissions, and relative capacity. The results show that the capital costs required to upgrade a pipeline can vary from tens of millions to billions of dollars depending on the length and capacity of the existing pipeline section, whether the existing pipeline already operates at or below its maximum allowable operating pressure, whether future demand is expected to increase or decrease, the network modification method selected, and pipe material costs. The delivered cost of energy to end users is impacted less by the levelized cost of transporting hydrogen blends than by the cost of the natural gas and hydrogen fuels being transported. The emissions impact of blending hydrogen into natural gas transmission networks scales proportionally with the amount of energy displaced with low-emission hydrogen (such as from natural gas with carbon capture and sequestration or electrolysis powered by nuclear, renewable, or geothermal electricity), therefore low blend ratios (e.g., < 20% vol. hydrogen) will result in low emissions impacts. Factors such as permitting and right-of-way costs, the proximity of the pipeline to hydrogen demand and production, and the compatibility of and/or retrofitting costs of end-use gas-fueled technologies will likely be greater drivers in determining whether converting a particular natural gas pipeline to carry hydrogen makes economic sense.

08 HYDROGEN↗
DOE OSTI2022

Repurposed dihydroorotate dehydrogenase inhibitors with efficacy against drug-resistant Acinetobacter baumannii

New antimicrobials are needed for the treatment of extensively drug-resistantAcinetobacter baumannii. The de novo pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) is a validated drug target for malaria and human autoimmune diseases. Here, we provide genetic evidence thatA. baumanniiDHODH (AbDHODH) is essential for bacterial survival in rodent infection models. We chemically validate the target by repurposing a unique library of ~450 triazolopyrimidine/imidazopyrimidine analogs developed for our malaria DHODH program to identify 21 compounds with submicromolar activity onAbDHODH. The most potent (DSM186, DHODH IC 50 28 nM) had a minimal inhibitory concentration of ≤1 µg/ml against geographically diverseA. baumanniistrains, including meropenem-resistant isolates. A structurally related analog (DSM161) with a long in vivo half-life conferred significant protection in the neutropenic mouse thigh infection model. Encouragingly, the development of resistance to these compounds was not identified in vitro or in vivo. Lastly, the X-ray structure ofAbDHODH bound to DSM186 was solved to 1.4 Å resolution. These data support the potential ofAbDHODH as a drug target for the development of antimicrobials for the treatment ofA. baumanniiand potentially other high-risk bacterial infections.

Acinetobacter baumannii↗