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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 19 records
All sourcesNASA NTRSDOE OSTI
DOE OSTI2016

The structure of a doripenem‐bound OXA‐51 class D β‐lactamase variant with enhanced carbapenemase activity

Abstract OXA‐51 is a class D β‐lactamase that is thought to be the native carbapenemase of Acinetobacter baumannii . Many variants of OXA‐51 containing active site substitutions have been identified from A. baumannii isolates, and some of these substitutions increase hydrolytic activity toward carbapenem antibiotics. We have determined the high‐resolution structures of apo OXA‐51 and OXA‐51 with one such substitution (I129L) with the carbapenem doripenem trapped in the active site as an acyl‐intermediate. The structure shows that acyl‐doripenem adopts an orientation very similar to carbapenem ligands observed in the active site of OXA‐24/40 (doripenem) and OXA‐23 (meropenem). In the OXA‐51 variant/doripenem complex, the indole ring of W222 is oriented away from the doripenem binding site, thereby eliminating a clash that is predicted to occur in wildtype OXA‐51. Similarly, in the OXA‐51 variant complex, L129 adopts a different rotamer compared to I129 in wildtype OXA‐51. This alternative position moves its side chain away from the hydroxyethyl moiety of doripenem and relieves another potential clash between the enzyme and carbapenem substrates. Molecular dynamics simulations of OXA‐51 and OXA‐51 I129L demonstrate that compared to isoleucine, a leucine at this position greatly favors a rotamer that accommodates the ligand. These results provide a molecular justification for how this substitution generates enhanced binding affinity for carbapenems, and therefore helps explain the prevalence of this substitution in clinical OXA‐51 variants.

June, Cynthia M.↗
DOE OSTI2019

Role of the Hydrophobic Bridge in the Carbapenemase Activity of Class D β-Lactamases

Class D carbapenemases are enzymes of the utmost clinical importance due to their ability to confer resistance to the last-resort carbapenem antibiotics. We investigated the role of the conserved hydrophobic bridge in the carbapenemase activity of OXA-23, the major carbapenemase of the important pathogen Acinetobacter baumannii . We show that substitution of the bridge residue Phe110 affects resistance to meropenem and doripenem and has little effect on MICs of imipenem. The opposite effect was observed upon substitution of the other bridge residue Met221. Complete disruption of the bridge by the F110A/M221A substitution resulted in a significant loss of affinity for doripenem and meropenem and to a lesser extent for imipenem, which is reflected in the reduced MICs of these antibiotics. In the wild-type OXA-23, the pyrrolidine ring of the meropenem tail forms a hydrophobic interaction with Phe110 of the bridge. Similar interactions would ensue with ring-containing doripenem but not with imipenem, which lacks this ring. Our structural studies showed that this interaction with the meropenem tail is missing in the F110A/M221A mutant. These data explain why disruption of the interaction between the enzyme and the carbapenem substrate impacts the affinity and MICs of meropenem and doripenem to a larger degree than those of imipenem. Our structures also show that the bridge directs the acylated carbapenem into a specific tautomeric conformation. Furthermore, it is not this conformation but rather the stabilizing interaction between the tail of the antibiotic and the hydrophobic bridge that contributes to the carbapenemase activity of class D β-lactamases.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

Standardized Residue Numbering and Secondary Structure Nomenclature in the Class D β-Lactamases

Over 1370 class D β-lactamases are currently known, and they pose a serious threat to the effective treatment of many infectious diseases, particularly in some pathogenic bacteria where evolving carbapenemase activity has been reported. Detailed understanding of their molecular biology, enzymology, and structural biology are critically important, but the lack of a standardized residue numbering scheme and inconsistent secondary structure annotation has made comparative analyses sometimes difficult and cumbersome. Compounding this, in the post-AlphaFold world where we currently find ourselves, an extraordinary wealth of detailed structural information on these enzymes is literally at our fingertips; therefore it is vitally important that a standard numbering system is in place to facilitate the accurate and straightforward analysis of their structures. In conclusion, here we present a residue numbering and secondary structure scheme for the class D enzymes based on the sequence and structure of OXA-48 and apply it to test targets to demonstrate the ease with which it can be used.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

Diversity in the Common Fold: Structural Insights into Class D β-Lactamases from Gram-Negative Pathogens

Class D β-lactamases (DBLs) represent a major threat to antibiotic efficacy by hydrolyzing β-lactam drugs, including last-resort carbapenems, thereby driving antimicrobial resistance in Gram-negative bacteria. The enzymes share a structurally conserved two-domain α/β architecture with seven active-site motifs and three flexible extended loops (the P-loop, Ω-loop, and newly designated B-loop) that surround the active site. While each of these loops is known to influence enzyme function, their coordinated roles have not been fully elucidated. To investigate the significance of their interplay, we compared the sequences and crystal structures of 40 DBLs from clinically relevant Gram-negative pathogens and performed molecular dynamics simulations on selected representatives. Combined structural and dynamical analyses revealed a strong correlation between B-loop architecture and carbapenemase activity in the pathogens Klebsiella and Acinetobacter, particularly regarding loop length and spatial organization. These findings emphasize the B-loop’s critical contribution, in concert with the P- and Ω-loops, in tuning active site versatility, substrate recognition, catalytic activity, and structural stability. A deeper understanding of how these motifs and loops govern DBL function may inform the development of novel antibiotics and inhibitors targeting this class of enzymes.

antibiotic resistance↗
DOE OSTI2023

Sulfonamidoboronic Acids as “Cross-Class” Inhibitors of an Expanded-Spectrum Class C Cephalosporinase, ADC-33, and a Class D Carbapenemase, OXA-24/40: Strategic Compound Design to Combat Resistance in Acinetobacter baumannii

Acinetobacter baumannii is a Gram-negative organism listed as an urgent threat pathogen by the World Health Organization (WHO). Carbapenem-resistant A. baumannii (CRAB), especially, present therapeutic challenges due to complex mechanisms of resistance to β-lactams. One of the most important mechanisms is the production of β-lactamase enzymes capable of hydrolyzing β-lactam antibiotics. Co-expression of multiple classes of β-lactamases is present in CRAB; therefore, the design and synthesis of “cross-class” inhibitors is an important strategy to preserve the efficacy of currently available antibiotics. To identify new, nonclassical β-lactamase inhibitors, we previously identified a sulfonamidomethaneboronic acid CR167 active against Acinetobacter-derived class C β-lactamases (ADC-7). The compound demonstrated affinity for ADC-7 with a K i = 160 nM and proved to be able to decrease MIC values of ceftazidime and cefotaxime in different bacterial strains. Herein, we describe the activity of CR167 against other β-lactamases in A. baumannii: the cefepime-hydrolysing class C extended-spectrum β-lactamase (ESAC) ADC-33 and the carbapenem-hydrolyzing OXA-24/40 (class D). These investigations demonstrate CR167 as a valuable cross-class (C and D) inhibitor, and the paper describes our attempts to further improve its activity. Five chiral analogues of CR167 were rationally designed and synthesized. The structures of OXA-24/40 and ADC-33 in complex with CR167 and select chiral analogues were obtained. The structure activity relationships (SARs) are highlighted, offering insights into the main determinants for cross-class C/D inhibitors and impetus for novel drug design.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

A pulsed current-mode class-D low-voltage high-bandwidth power amplifier for portable NMR systems

Low-field NMR has seen growing interest in recent years, especially for portable applications. The lower homogeneity magnets used for portable applications require short RF pulses to ensure enough transmit bandwidth to excite the sample volume and also support short echo periods. Furthermore, the preferred use of a high-Q coil to improve signal-to-noise ratio (SNR) prolongs the pulse transients. Thus, at such low Larmor frequencies, the excitation pulse transients become comparable or longer than the pulse length, such that the transmit bandwidth begins to limit measurement SNR. This paper describes the design of a pulsed current-mode class-D power (PCMCD) transmitter that addresses this issue by generating high power in a tuned sample coil while maintaining short transients, thus resulting in high output bandwidth. The transmitter also uses a charge recycling mechanism to maximize power efficiency for RF train excitation, which also results in faster pulse repetition rate and reduces allowable echo time. In this work, experimental results from a small form-factor PCMCD transmitter are presented. This design generates a peak RF power of 240 W into a 9.16 µH coil at 4 MHz while operating off a single 12 V power supply. NMR measurement results using the transmitter are also described, showing minimum achievable echo time of 70 µs and 25 µs depending on the transmitter mode of operation.

47 OTHER INSTRUMENTATION↗
DOE OSTI2021

Unique Diacidic Fragments Inhibit the OXA-48 Carbapenemase and Enhance the Killing of Escherichia coli Producing OXA-48

Despite the advances in β-lactamase inhibitor development, limited options exist for the class D carbapenemase known as OXA-48. OXA-48 is one of the most prevalent carbapenemases in carbapenem-resistant Enterobacteriaceae infections and is not susceptible to most available β-lactamase inhibitors. Here, we screened various low-molecular-weight compounds (fragments) against OXA-48 to identify functional scaffolds for inhibitor development. Several biphenyl-, naphthalene-, fluorene-, anthraquinone-, and azobenzene-based compounds were found to inhibit OXA-48 with low micromolar potency despite their small size. Co-crystal structures of OXA-48 with several of these compounds revealed key interactions with the carboxylate-binding pocket, Arg214, and various hydrophobic residues of β-lactamase that can be exploited in future inhibitor development. A number of the low-micromolar-potency inhibitors, across different scaffolds, synergize with ampicillin to kill Escherichia coli expressing OXA-48, albeit at high concentrations of the respective inhibitors. Additionally, several compounds demonstrated micromolar potency toward the OXA-24 and OXA-58 class D carbapenemases that are prevalent in Acinetobacter baumannii . In conclusion, this work provides foundational information on a variety of chemical scaffolds that can guide the design of effective OXA-48 inhibitors that maintain efficacy as well as potency toward other major class D carbapenemases.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2026

The Novel Carbapenem, JDB/PQ-1-219, Has Potent Broad Spectrum Activity against Multi-Drug Resistant Acinetobacter baumannii

Carbapenem resistance in Acinetobacter baumannii, driven largely by class D, along with class A and class B β- lactamases, has severely compromised the utility of these last resort antibiotics. As a result, infections caused by such pathogens are characterized by extremely high mortality rates. Here we describe the antimicrobial activity of the novel C5 methyl-substituted carbapenem JDB/PQ-1−219 against multidrug resistant A. baumannii and the mechanism of its interaction with its major carbapenemase, OXA-23. JDB/PQ-1-219 exhibits potent antimicrobial activity against A. baumannii producing various carbapenemases, with MICs that are all in the clinically susceptible range. The compound has unrestricted ingress through porins and avoids egress by efflux pumps, a unique property when compared to all commercial carbapenems. Kinetic experiments demonstrated that unlike for other carbapenems, acylation of OXA-23 by JDB/ PQ-1-219 is monophasic, and mass spectrometry studies showed that this results from the conversion of all enzyme into a reversible tetrahedral intermediate which gradually transitions into the stable acyl-enzyme complex. No deacylation of this complex is observed over a physiologically relevant time period, making JDB/PQ-1−219 an extremely potent inhibitor of OXA-23. Time-resolved crystallography revealed fine details of active site dynamics, leading to complete inhibition of the enzyme. Together, these studies identify JDB/PQ-1-219 as a uniquely effective novel carbapenem with clinically significant levels of activity against multidrug resistant A. baumannii.

Acinetobacter baumannii↗
DOE OSTI2023

Modeling and analysis of the tritium fuel cycle for ARC- and STEP-class D-T fusion power plants

Abstract The limited tritium resources available for the first fusion power plants (FPPs) make fuel self-sufficiency and tritium inventory minimization leading issues in FPP design. This work builds on the model proposed by Abdou et al (2020 Nucl. Fusion 61 013001), which analyzed the fuel cycle (FC) of a DEMOnstration nuclear FPP-class FPP with a time-dependent system-level model. Here, we use a modified version of their model to analyze the FC of an Affordable, Robust, Compact (ARC)-class tokamak and two versions of a Spherical Tokamak for Energy Production (STEP)-class tokamak. The ARC-class tokamak breeds tritium in a 2LiF + BeF 2 liquid immersion blanket, while the STEP-class tokamak breeds tritium utilizing either a liquid-lithium blanket design or an encapsulated breeding blanket. A time-dependent system-level model is developed in Matlab Simulink ® to simulate the evolution of tritium flows and tritium inventories in the FC. The main goals of this work are to assess tritium self-sufficiency of the ARC- and STEP-class designs and to determine quantitative design requirements that can be used to analyze the adequacy of a proposed FC system. These design requirements are aimed at achieving a low tritium inventory doubling time ( t d ) and a low start-up inventory ( I s t a r t u p ) while keeping the required tritium breeding ratio (TBR r ) as low as possible. We also consider how improvements in FC technology and POs affect TBR r and I s t a r t u p . The model results show that TBR r for ARC- and STEP-class FPPs should be achievable if the tritium burn efficiency (TBE) reaches 0.5%–1% (TBR r < 1.2). This assumes significant, but attainable, improvements over current abilities. However, the model results indicate that an FPP must achieve ambitious performance targets, including FPP availability > 70%, tritium processing time < 4 h, and the implementation of direct internal recycling (DIR). If future research yields major improvements to achievable TBE, it may be possible to achieve tritium self-sufficiency while operating at lower availability and without implementing DIR.

Physics↗
DOE OSTI2025

Dual mechanism of the OXA-23 carbapenemase inhibition by the carbapenem NA-1-157

Carbapenem-resistant Acinetobacter baumannii continues to be a leading cause of life-threatening infections that result in high mortality rates. The major cause of carbapenem resistance in this pathogen is the production of class D carbapenemases, enzymes that inactivate the last resort carbapenem antibiotics, thus significantly diminishing the available therapeutic options. In this study, we evaluated the interaction of OXA-23, the most widely disseminated class D carbapenemase in A. baumannii clinical isolates, with the atypically modified carbapenem, NA-1-157. The MICs of this compound against strains producing OXA-23 were reduced from highly resistant levels observed for the commercial carbapenems meropenem and imipenem (16–128 µg/mL) to sensitive or intermediate levels (2–4 µg/mL). Kinetic studies showed that NA-1-157 inhibits the enzyme due to a significant decrease (>2,000-fold) in the deacylation rate relative to its closest structural analog, meropenem. Structural studies and molecular dynamics simulations demonstrated that inhibition is caused by both the inability of a water molecule to get close enough to the scissile bond to perform deacylation and by partial decarboxylation of the catalytic lysine residue upon formation of the acyl-enzyme intermediate.

Acinetobacter baumannii↗
DOE OSTI2016

Holographic correspondence in topological superconductors

We analytically derive a compatible family of effective field theories that uniquely describe topological superconductors in 3D, their 2D boundary and their 1D defect lines. We start by deriving the topological field theory of a 3D topological superconductor in class DIII, which is consistent with its symmetries. Then we identify the effective theory of a 2D topological superconductor in class D living on the gapped boundary of the 3D system. By employing the holographic correspondence we derive the effective chiral conformal field theory that describes the gapless modes living on the defect lines or effective boundary of the class D topological superconductor. We demonstrate that the chiral central charge is given in terms of the 3D winding number of the bulk which by its turn is equal to the Chern number of its gapped boundary.

71 CLASSICAL AND QUANTUM MECHANICS, GENERAL PHYSIC↗
DOE OSTI2024

Decarboxylation of the Catalytic Lysine Residue by the C5α-Methyl-Substituted Carbapenem NA-1-157 Leads to Potent Inhibition of the OXA-58 Carbapenemase

Antibiotic resistance in bacteria is a major global health concern. The wide spread of carbapenemases, bacterial enzymes that degrade the last-resort carbapenem antibiotics, is responsible for multidrug resistance in bacterial pathogens and has further significantly exacerbated this problem. Acinetobacter baumannii is one of the leading nosocomial pathogens due to the acquisition and wide dissemination of carbapenem-hydrolyzing class D β-lactamases, which have dramatically diminished available therapeutic options. Thus, new antibiotics that are active against multidrug-resistantA. baumannii and carbapenemase inhibitors are urgently needed. Here we report characterization of the interaction of the C5α-methyl-substituted carbapenem NA-1-157 with one of the clinically important class D carbapenemases, OXA-58. Antibiotic susceptibility testing shows that the compound is more potent than commercial carbapenems against OXA-58-producingA. baumannii, with a clinically sensitive MIC value of 1 μg/mL. Kinetic studies demonstrate that NA-1-157 is a very poor substrate of the enzyme due mainly to a significantly reduced deacylation rate. Mass spectrometry analysis shows that inhibition of OXA-58 by NA-1-157 proceeds through both the classical acyl-enzyme intermediate and a reversible covalent species. Time-resolved X-ray crystallographic studies reveal that upon acylation of the enzyme, the compound causes progressive decarboxylation of the catalytic lysine residue, thus severely impairing deacylation. Overall, this study demonstrates that the carbapenem NA-1-157 is highly resistant to degradation by the OXA-58 carbapenemase.

Acinetobactor↗
DOE OSTI2022

C6 Hydroxymethyl-Substituted Carbapenem MA-1-206 Inhibits the Major Acinetobacter baumannii Carbapenemase OXA-23 by Impeding Deacylation

Acinetobacter baumannii has become a major nosocomial pathogen, as it is often multidrug-resistant, which results in infections characterized by high mortality rates. The bacterium achieves high levels of resistance to β-lactam antibiotics by producing β-lactamases, enzymes which destroy these valuable agents. Historically, the carbapenem family of b-lactam antibiotics have been the drugs of choice for treating A. baumannii infections. However, their effectiveness has been significantly diminished due to the pathogen’s production of carbapenem-hydrolyzing class D β-lactamases (CHDLs); thus, new antibiotics and inhibitors of these enzymes are urgently needed. Here, we describe a new carbapenem antibiotic, MA-1-206, in which the canonical C6 hydroxyethyl group has been replaced with hydroxymethyl. The antimicrobial susceptibility studies presented here demonstrated that this compound is more potent than meropenem and imipenem against A. baumannii producing OXA-23, the most prevalent CHDL of this pathogen, and also against strains producing the CHDL OXA-24/40 and the class B metallo-β-lactamase VIM-2. Our kinetic and mass spectrometry studies revealed that this drug is a reversible inhibitor of OXA-23, where inhibition takes place through a branched pathway. X-ray crystallographic studies, molecular docking, and molecular dynamics simulations of the OXA-23-MA-1-206 complex show that the C6 hydroxymethyl group forms a hydrogen bond with the carboxylated catalytic lysine of OXA-23, effectively preventing deacylation. These results provide a promising strategy for designing a new generation of CHDL-resistant carbapenems to restore their efficacy against deadly A. baumannii infections. Carbapenem antibiotics are the drugs of choice for treatment of deadly infections caused by Gram-negative bacteria. However, their efficacy is severely compromised by the wide spread of carbapenem-hydrolyzing class D β-lactamases (CHDLs). The importance of this research is the discovery that substitution of the canonical hydroxyethyl group of carbapenems by a hydroxymethyl significantly enhances stability against inactivation by the major CHDL of Acinetobacter baumannii, OXA-23. These results provide a novel strategy for designing next-generation, carbapenemase-stable carbapenems to fight multidrug-resistant infections caused by Gram-negative pathogens

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Prediction of intrinsic topological superconductivity in Mn-doped GeTe monolayer from first-principles

The recent discovery of topological superconductors (TSCs) has sparked enormous interest. The realization of TSC requires a delicate tuning of multiple microscopic parameters, which remains a great challenge. Here, we develop a first-principles approach to quantify realistic conditions of TSC by solving self-consistently Bogoliubov-de Gennes equation based on a Wannier function construction of band structure, in presence of Rashba spin-orbit coupling, Zeeman splitting and electron-phonon coupling. We further demonstrate the power of this method by predicting the Mn-doped GeTe (Ge 1- x Mn x Te) monolayer—a well-known dilute magnetic semiconductor showing superconductivity under hole doping—to be a Class D TSC with Chern number of -1 and chiral Majorana edge modes. By constructing a first-principles phase diagram in the parameter space of temperature and Mn concentration, we propose the TSC phase can be induced at a lower-limit transition temperature of ~40 mK and the Mn concentration of x ~0.015%. Our approach can be generally applied to TSCs with a phonon-mediated pairing, providing useful guidance for future experiments.

Chemistry↗
DOE OSTI2021

Development of a Nitrogen and Magnesium Oxide based Class A, B & D Suffocating Fire System (SFSS) for Gloveboxes

Testing related to the development and performance of a “Proof of Concept” Nitrogen/Magnesium Oxide Suffocating Fire System (SFSS) was conducted at Fire and Pump Service Group (FPSG) located in Rancho Dominguez, California. The SFSS Engineering Team (SFSSET), consisting of FPSG and Los Alamos National Laboratory (LANL) personnel researched, developed a prototype, and conducted testing to determine effective means to deliver magnesium oxide (MgO) sand into a glovebox (GB) in a class D fire event. The prototypes development also established the effective coverage area of a magnesium oxide suppression system as well as demonstrated that the GB inert atmosphere could be maintained during and after the release of the MgO sand to control Class A, B and D fires. Previous testing conducted on nitrogen based SFSS provided evidence that the nitrogen based SFSS controlled Class A and B fires (Ralph Clayton, Los Alamos National Laboratory, Brandon Troc and Frank Broidy, Fire and Pump Service Group 2020).Final testing was conducted within a mock GB capable of simulating an inert glovebox atmosphere. Testing demonstrated that the inert atmosphere can be maintained during and after discharge of the MgO sand over a coverage area.

98 NUCLEAR DISARMAMENT, SAFEGUARDS, AND PHYSICAL P↗