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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 145 records · Page 8
All sourcesNASA NTRSDOE OSTI
NASA NTRS2011

Assessment of Gamma Radiation Resistance of Spores Isolated from the Spacecraft Assembly Facility During MSL Assembly

Spore forming bacteria, a common inhabitant of spacecraft assembly facilities, are known to tolerate extreme environmental conditions such as radiation, desiccation, and high temperatures. Since the Viking era (early 1970's), spores have been utilized to assess the degree and level of microbiological contamination on spacecraft and their associated spacecraft assembly facilities. There is a growing concern that desiccation and extreme radiation resistant spore forming microorganisms associated with spacecraft surfaces can withstand space environmental conditions and subsequently proliferate on another solar body. Such forward contamination would certainly jeopardize future life detection or sample return technologies. It is important to recognize that different classes of organisms are critical while calculating the probability of contamination, and methods must be devised to estimate their abundances. Microorganisms can be categorized based on radiation sensitivity as Type A, B, C, and D. Type C represents spores resistant to radiation (10% or greater survival above 0.8 Mrad gamma radiation). To address these questions we have purified 96 spore formers, isolated during planetary protection efforts of Mars Science Laboratory assembly for gamma radiation resistance. The spores purified and stored will be used to generate data that can be used further to model and predict the probability of forward contamination.

spacecraft assembly↗
NASA NTRS2004

A Survey of Staphylococcus sp and its Methicillin Resistance aboard the International Space Station

Background: Within the past few years, methicillin-resistant Staphylococcus aureus has emerged in environments with susceptible hosts in close proximity, such as hospitals and nursing homes. As the International Space Station (ISS) represents a semi-closed environment with a high level of crewmember interaction, an evaluation of isolates of clinical and environmental Staphylococcus aureus and coagulase negative Staphylococcus was performed to determine if this trend was also present in astronauts occupying ISS or on surfaces of the space station itself. Methods: Identification of isolates was completed using VITEK (GPI cards, BioMerieux), 16S ribosomal DNA analysis (MicroSeq 500, ABI), and Rep-PCR DNA fingerprinting (Divemilab, Bacterial Barcodes). Susceptibility tests were performed using VITEK (GPS-105 cards, BioMerieux) and resistance characteristics were evaluated by testing for the presence of the mecA gene (PBP2' MRSA test kit, Oxoid). Results: Rep-PCR analysis indicated the transfer of S. aureus between crewmembers and between crewmembers and ISS surfaces. While a variety of S. aureus were identified from both the crewmembers and environment, evaluations of the microbial population indicated minimal methicillin resistance. Results of this study indicated that within the semi-closed ISS environment, transfer of bacteria between crewmembers and their environment has been occurring, although there was no indication of a high concentration of methicillin resistant Staphylococcus species. Conclusions: While this study suggests that the spread of methicillin resistant S. aureus is not currently a concern aboard ISS, the increasing incidence of Earth-based antibiotic resistance indicates a need for continued clinical and environmental monitoring.

Bassinger, V. J.↗
DOE OSTI2021

The Enzymatic Activity of Inosine 5'-Monophosphate Dehydrogenase May Not Be a Vulnerable Target for Staphylococcus aureus Infections

Many bacterial pathogens, including Staphylococcus aureus, require inosine 5'-monophosphate dehydrogenase (IMPDH) for infection, making this enzyme a promising new target for antibiotics. Although potent selective inhibitors of bacterial IMPDHs have been reported, relatively few have displayed antibacterial activity. Here we use structure-informed design to obtain inhibitors of S. aureus IMPDH (SaIMPDH) that have potent antibacterial activity (minimal inhibitory concentrations less than 2 μM) and low cytotoxicity in mammalian cells. The physicochemical properties of the most active compounds were within typical Lipinski/Veber space, suggesting that polarity is not a general requirement for achieving antibacterial activity. In this work, five compounds failed to display activity in mouse models of septicemia and abscess infection. Inhibitor-resistant S. aureus strains readily emerged in vitro. Resistance resulted from substitutions in the cofactor/inhibitor binding site of SaIMPDH, confirming on-target antibacterial activity. These mutations decreased the binding of all inhibitors tested, but also decreased catalytic activity. Nonetheless, the resistant strains had comparable virulence to wild-type bacteria. Surprisingly, strains expressing catalytically inactive SaIMPDH displayed only a mild virulence defect. Collectively these observations question the vulnerability of the enzymatic activity of SaIMPDH as a target for the treatment of S. aureus infections, suggesting other functions of this protein may be responsible for its role in infection.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

Solution characterization of the dynamic conjugative entry exclusion protein TraG

The R100 plasmid and the secretion system it encodes are representative of F-like conjugative type IV secretion systems for the transmission of mobile DNA elements in gram-negative bacteria, serving as a major contributor to the spread of antibiotic resistance in bacterial pathogens. The TraG protein of F-like systems consists of a membrane-bound N-terminal domain and a periplasmic C-terminal domain, denoted TraG*. TraG* is essential in preventing redundant DNA transfer through a process termed entry exclusion. In the donor cell, it interacts with TraN to facilitate mating pair stabilization; however, if a mating pore forms between bacteria with identical plasmids, TraG* interacts with its cognate TraS in the inner membrane of the recipient bacterium to prevent redundant donor–donor conjugation. Structural studies of TraG* from the R100 plasmid have revealed the presence of a dynamic region between the N- and C-terminal domains of TraG. Thermofluor, circular dichroism, collision-induced unfolding–mass spectrometry, and size exclusion chromatography linked to multiangle light scattering and small angle x-ray scattering experiments indicated an N-terminal truncation mutant displayed higher stability and less disordered content relative to full-length TraG*. The 45 N-terminal residues of TraG* are hypothesized to serve as part of a flexible linker between the two independently functioning domains.

59 BASIC BIOLOGICAL SCIENCES↗
NASA NTRS2005

Intraspecific differences in bacterial responses to modelled reduced gravity

AIMS: Bacteria are important residents of water systems, including those of space stations which feature specific environmental conditions, such as lowered effects of gravity. The purpose of this study was to compare responses with modelled reduced gravity of space station, water system bacterial isolates with other isolates of the same species. METHODS AND RESULTS: Bacterial isolates, Stenotrophomonas paucimobilis and Acinetobacter radioresistens, originally recovered from the water supply aboard the International Space Station (ISS) were grown in nutrient broth under modelled reduced gravity. Their growth was compared with type strains S. paucimobilis ATCC 10829 and A. radioresistens ATCC 49000. Acinetobacter radioresistens ATCC 49000 and the two ISS isolates showed similar growth profiles under modelled reduced gravity compared with normal gravity, whereas S. paucimobilis ATCC 10829 was negatively affected by modelled reduced gravity. CONCLUSIONS: These results suggest that microgravity might have selected for bacteria that were able to thrive under this unusual condition. These responses, coupled with impacts of other features (such as radiation resistance and ability to persist under very oligotrophic conditions), may contribute to the success of these water system bacteria. SIGNIFICANCE AND IMPACT OF THE STUDY: Water quality is a significant factor in many environments including the ISS. Efforts to remove microbial contaminants are likely to be complicated by the features of these bacteria which allow them to persist under the extreme conditions of the systems.

Non-NASA Center↗
DOE OSTI2022

Classification of bacterial plasmid and chromosome derived sequences using machine learning

Plasmids are important genetic elements that facilitate horizonal gene transfer between bacteria and contribute to the spread of virulence and antimicrobial resistance. Most bacterial genome sequences in the public archives exist in draft form with many contigs, making it difficult to determine if a contig is of chromosomal or plasmid origin. Using a training set of contigs comprising 10,584 chromosomes and 10,654 plasmids from the PATRIC database, we evaluated several machine learning models including random forest, logistic regression, XGBoost, and a neural network for their ability to classify chromosomal and plasmid sequences using nucleotide k-mers as features. Based on the methods tested, a neural network model that used nucleotide 6-mers as features that was trained on randomly selected chromosomal and plasmid subsequences 5kb in length achieved the best performance, outperforming existing out-of-the-box methods, with an average accuracy of 89.38% ± 2.16% over a 10-fold cross validation. The model accuracy can be improved to 92.08% by using a voting strategy when classifying holdout sequences. In both plasmids and chromosomes, subsequences encoding functions involved in horizontal gene transfer—including hypothetical proteins, transporters, phage, mobile elements, and CRISPR elements—were most likely to be misclassified by the model. This study provides a straightforward approach for identifying plasmid-encoding sequences in short read assemblies without the need for sequence alignment-based tools.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Structure of the essential inner membrane lipopolysaccharide–PbgA complex

Lipopolysaccharide (LPS) resides in the outer membrane of Gram-negative bacteria where it is responsible for barrier function. LPS can cause death as a result of septic shock, and its lipid A core is the target of polymyxin antibiotics. Despite the clinical importance of polymyxins and the emergence of multidrug resistant strains, our understanding of the bacterial factors that regulate LPS biogenesis is incomplete. Here we characterize the inner membrane protein PbgA and report that its depletion attenuates the virulence of Escherichia coli by reducing levels of LPS and outer membrane integrity. In contrast to previous claims that PbgA functions as a cardiolipin transporter, our structural analyses and physiological studies identify a lipid A-binding motif along the periplasmic leaflet of the inner membrane. Synthetic PbgA-derived peptides selectively bind to LPS in vitro and inhibit the growth of diverse Gram-negative bacteria, including polymyxin-resistant strains. Proteomic, genetic and pharmacological experiments uncover a model in which direct periplasmic sensing of LPS by PbgA coordinates the biosynthesis of lipid A by regulating the stability of LpxC, a key cytoplasmic biosynthetic enzyme. In summary, we find that PbgA has an unexpected but essential role in the regulation of LPS biogenesis, presents a new structural basis for the selective recognition of lipids, and provides opportunities for future antibiotic discovery.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Development of LpxH Inhibitors Chelating the Active Site Dimanganese Metal Cluster of LpxH

Abstract Despite the widespread emergence of multidrug‐resistant nosocomial Gram‐negative bacterial infections and the major public health threat it brings, no new class of antibiotics for Gram‐negative pathogens has been approved over the past five decades. Therefore, there is an urgent medical need for developing effective novel antibiotics against multidrug‐resistant Gram‐negative pathogens by targeting previously unexploited pathways in these bacteria. To fulfill this crucial need, we have been investigating a series of sulfonyl piperazine compounds targeting LpxH, a dimanganese‐containing UDP‐2,3‐diacylglucosamine hydrolase in the lipid A biosynthetic pathway, as novel antibiotics against clinically important Gram‐negative pathogens. Inspired by a detailed structural analysis of our previous LpxH inhibitors in complex with K. pneumoniae LpxH ( Kp LpxH), here we report the development and structural validation of the first‐in‐class sulfonyl piperazine LpxH inhibitors, JH‐LPH‐45 ( 8 ) and JH‐LPH‐50 ( 13 ), that achieve chelation of the active site dimanganese cluster of Kp LpxH. The chelation of the dimanganese cluster significantly improves the potency of JH‐LPH‐45 ( 8 ) and JH‐LPH‐50 ( 13 ). We expect that further optimization of these proof‐of‐concept dimanganese‐chelating LpxH inhibitors will ultimately lead to the development of more potent LpxH inhibitors for targeting multidrug‐resistant Gram‐negative pathogens.

Pharmacology & Pharmacy↗
DOE OSTI2023

Phage therapy: From biological mechanisms to future directions

Increasing antimicrobial resistance rates have revitalized bacteriophage (phage) research, the natural predators of bacteria discovered over 100 years ago. In order to use phages therapeutically, they should (1) preferably be lytic, (2) kill the bacterial host efficiently, and (3) be fully characterized to exclude side effects. Developing therapeutic phages takes a coordinated effort of multiple stakeholders. Herein, we review the state of the art in phage therapy, covering biological mechanisms, clinical applications, remaining challenges, and future directions involving naturally occurring and genetically modified or synthetic phages.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Structural basis of colibactin activation by the ClbP peptidase

Abstract Colibactin, a DNA cross-linking agent produced by gut bacteria, is implicated in colorectal cancer. Its biosynthesis uses a prodrug resistance mechanism: a non-toxic precursor assembled in the cytoplasm is activated after export to the periplasm. This activation is mediated by ClbP, an inner-membrane peptidase with an N-terminal periplasmic catalytic domain and a C-terminal three-helix transmembrane domain. Although the transmembrane domain is required for colibactin activation, its role in catalysis is unclear. Our structure of full-length ClbP bound to a product analog reveals an interdomain interface important for substrate binding and enzyme stability and interactions that explain the selectivity of ClbP for the N -acyl- d -asparagine prodrug motif. Based on structural and biochemical evidence, we propose that ClbP dimerizes to form an extended substrate-binding site that can accommodate a pseudodimeric precolibactin with its two terminal prodrug motifs in the two ClbP active sites, thus enabling the coordinated activation of both electrophilic warheads.

Biochemistry & Molecular Biology↗
NASA NTRS2005

Population dynamics of transgenic strain Escherichia coli Z905/pPHL7 in freshwater and saline lake water microcosms with differing microbial community structures

Populations of Escherichia coli Z905/pPHL7, a transgenic microorganism, were heterogenic in the expression of plasmid genes when adapting to the conditions of water microcosms of various mineralization levels and structure of microbial community. This TM has formed two subpopulations (ampicillin-resistant and ampicillin-sensitive) in every microcosm. Irrespective of mineralization level of a microcosm, when E. coli Z905/pPHL7 alone was introduced, the ampicillin-resistant subpopulation prevailed, while introduction of the TM together with indigenous bacteria led to the dominance of the ampicillin-sensitive subpopulation. A high level of lux gene expression maintained longer in the freshwater microcosms than in sterile saline lake water microcosms. A horizontal gene transfer has been revealed between the jointly introduced TM and Micrococcus sp. 9/pSH1 in microcosms with the Lake Shira sterile water. c2005 COSPAR. Published by Elsevier Ltd. All rights reserved.

Ecosystem↗
NASA NTRS1972

Resistance of soil microorganisms to starvation.

Most groups of soil microorganisms died when exposed to prolonged starvation in a carbon-free solution, but the relative abundance of Bacillus and actinomycetes increased with time. Certain nonspore-forming bacteria also persisted. The ability of individual soil isolates to endure starvation in solution was not correlated with their glycogen content or rate of endogenous respiration. However, cells of the resistant populations were rich in poly-beta-hydroxybutyrate, whereas the starvation-susceptible bacteria generally contained little of this substance. Poly-beta-hydroxybutyrate was used rapidly in cells deprived of exogenous sources of carbon.

Chen, M.↗
DOE OSTI2020

Current challenges and future opportunities of phage therapy

ABSTRACT Antibiotic resistance is a major public health challenge worldwide, whose implications for global health might be devastating if novel antibacterial strategies are not quickly developed. As natural predators of bacteria, (bacterio)phages may play an essential role in escaping such a dreadful future. The rising problem of antibiotic resistance has revived the interest in phage therapy and important developments have been achieved over the last years. But where do we stand today and what can we expect from phage therapy in the future? This is the question we set to answer in this review. Here, we scour the outcomes of human phage therapy clinical trials and case reports, and address the major barriers that stand in the way of using phages in clinical settings. We particularly address the potential of phage resistance to hinder phage therapy and discuss future avenues to explore the full capacity of phage therapy.

Pires, Diana P.↗
DOE OSTI2021

A global metagenomic map of urban microbiomes and antimicrobial resistance

We present a global atlas of 4,728 metagenomic samples from mass-transit systems in 60 cities over 3 years, representing the first systematic, worldwide catalog of the urban microbial ecosystem. This atlas provides an annotated, geospatial profile of microbial strains, functional characteristics, antimicrobial resistance (AMR) markers, and genetic elements, including 10,928 viruses, 1,302 bacteria, 2 archaea, and 838,532 CRISPR arrays not found in reference databases. We identified 4,246 known species of urban microorganisms and a consistent set of 31 species found in 97% of samples that were distinct from human commensal organisms. Profiles of AMR genes varied widely in type and density across cities. Cities showed distinct microbial taxonomic signatures that were driven by climate and geographic differences. These results constitute a high-resolution global metagenomic atlas that enables discovery of organisms and genes, highlights potential public health and forensic applications, and provides a culture-independent view of AMR burden in cities.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Design and Evaluation of Pyridinyl Sulfonyl Piperazine LpxH Inhibitors with Potent Antibiotic Activity Against Enterobacterales

Enterobacterales, a large order of Gram-negative bacteria, including Escherichia coli and Klebsiella pneumoniae, are major causes of urinary tract and gastrointestinal infections, pneumonia, and other diseases in healthcare settings and communities. ESBL-producing Enterobacterales and carbapenem-resistant Enterobacterales can break down commonly used antibiotics, with some strains being resistant to all available antibiotics. This public health threat necessitates the development of novel antibiotics, ideally targeting new pathways in these bacteria. Gram-negative bacteria possess an outer membrane enriched with lipid A, a saccharolipid that serves as the membrane anchor of lipopolysaccharides and the active component of the bacterial endotoxin, causing septic shock. The biosynthesis of lipid A is crucial for the viability of Gram-negative bacteria, and as an essential enzyme in this process, LpxH has emerged as a promising target for developing novel antibiotics against multidrugresistant Gram-negative pathogens. Here, we report the development of pyridinyl sulfonyl piperazine LpxH inhibitors. Among them, ortho-substituted pyridinyl compounds significantly boost LpxH inhibition and antibiotic activity over the original phenyl series. Structural and QM/MM analyses reveal that these improved activities are primarily due to the enhanced interaction between F141 of the LpxH insertion lid and the pyridinyl group. Incorporation of the N-methyl-N-phenyl-methanesulfonamide moiety into the pyridinyl sulfonyl piperazine backbone results in JHLPH- 106 and JH-LPH-107, both of which exhibit potent antibiotic activity against wild-type Enterobacterales such as K. pneumoniae and E. coli. JH-LPH-107 exhibits a low rate of spontaneous resistance and a high safety window in vitro, rendering it an excellent lead for further clinical development.

60 APPLIED LIFE SCIENCES↗
NASA NTRS2009

Evaluation of the Biocidal Efficacy of Different Forms of Silver Against Cupriavidus (formerly Wautersia) Species Bacteria

Contingency Water Containers (CWCs) are used to store potable and technical water that is transferred to the International Space Station (ISS) from the Shuttle orbiter vehicles. When CWCs are filled, water from the orbiter galley is passed through an ion exchange/activated carbon cartridge that removes the residual iodine biocide used on Shuttle before silver biocide is added. Removal of iodine and addition of silver is necessary to inhibit microbial growth inside CWCs and maintain compatibility with the water systems in the Russian segment of ISS. As part of nominal water transfer activities, crewmembers collect samples from several CWCs for postflight analysis. Results from the analysis of water transfer samples collected during the docked phases of STS-118/13A.1 and STS-120/10A showed that several of the CWCs contained up to 10(exp 4) CFU/mL of bacteria despite the fact that the silver concentrations in the CWCs were within acceptable limits. The samples contained pure cultures of a single bacteria, a Cupriavidus (formerly Wautersia) species that has been shown to be resistant to metallic biocides. As part of the investigation into the cause and remediation of the bacterial contamination in these CWCs, ground studies were initiated to evaluate the resistance of the Cupriavidus species to the silver biocides used on ISS and to determine the minimum effective concentration for the different forms of silver present in the biocides. The initial findings from those experiments are discussed herein.

Gazda, Daniel B.↗