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All sourcesNASA NTRSDOE OSTI
DOE OSTI2025

The ability of Salmonella enterica subsp. enterica strains to form biofilms on abiotic surfaces and their susceptibility to selected essential oil components

Abstract The ability of Salmonella enterica subsp. enterica to persist and form biofilms on different surfaces can constitute a source of food contamination, being an issue of global concern. The objective of this study was to understand the biofilm formation profile of 14 S. enterica strains among different serovars and sources and to evaluate the ability of essential oil (EO) components (carveol, citronellol, and citronellal) to disinfect the biofilms formed on stainless steel and polypropylene surfaces. All the strains were able to form biofilms with counts between 5.34 to 6.78 log CFU cm−2. Then, the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of EO components were evaluated on two selected strains. All compounds inhibited the growth of Salmonella Typhimurium (strain 1; MIC = 800–1000 µg ml−1) and Salmonella Enteritidis (strain 5; MIC = 400–1000 µg ml−1) and only carveol showed bactericidal activity against strains 1 and 5 (MBC = 1200 µg ml−1). Biofilms were exposed to the EO components at 10 × MIC for 30 min and polypropylene surfaces were more difficult to disinfect showing reductions between 0.9 and <1.2 log CFU cm−2. In general, the S. enterica biofilms demonstrated a significant tolerance to disinfection, demonstrating their high degree of recalcitrance on food processing surfaces.

Pérez-Lavalle, Liliana (ORCID:0000000344825031)↗
DOE OSTI2023

Comparative evaluation of antimicrobial activity of human granulysin, bovine and porcine NK-lysins against Shiga toxin-producing Escherichia coli O157:H7

Shiga toxin-producing Escherichia coli (STEC) O157:H7 (O157) is a foodborne pathogen causing human disease ranging from hemorrhagic colitis and hemolytic uremic syndrome to kidney failure, while remaining harmless to cattle, its primary reservoir. The severity of the human disease associated mainly with Shiga toxin production and a global emergence of antibiotic resistant STEC highlights the need for effective non-antibiotic, pre-harvest strategies to reduce O157 in cattle, the principal source of human infection. Towards this goal three synthetic antimicrobial peptides (AMPs): human granulysin (hGRNL), bovine NK-lysin (bNK2A), and porcine NK-lysin (pNKL), were tested in vitro against O157 isolates. As expected, circular dichroism spectroscopy findings were consistent with a predominantly α-helical conformation for all three AMPs in an environment mimicking bacterial outer surface or liposaccharides. The minimum inhibitory concentrations (MIC) and minimum bactericidal concentrations of hGRNL (200 μM), bNK2A (12.5 μM against strain 86–24 and 25 μM against EDL933), and pNKL (6.25 μM) were determined using the Clinical and Laboratory Standards Institute broth microdilution method in Müeller-Hinton broth (cation-adjusted). The bNK2A and pNKL AMPs did not induce Shiga toxin expression in O157 at MIC, as there was a significant decrease or no change in toxin expression following 4- or 20 h incubation with the AMPs; bNK2A p <0.0001 (4 h) and p = 0.4831 (20 h); pNKL p <0.0001 (4 h) and p = 0.0001 (20 h). Propidium iodide uptake assay revealed faster O157 membrane damage or killing kinetics with bNK2A and pNKL compared to hGRNL. Nonetheless, transmission electron microscopy demonstrated that all three AMPs mediated damage to O157 membranes. In contrast, the three AMPs showed minimal cytotoxicity (<2%) against cattle red blood cells at tested concentrations (0.39–50 μM). Overall, our results demonstrate the potential for bNK2A and pNKL to be further developed into novel non-antibiotic agents to reduce O157 shedding in cattle.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

A Rapid and High Throughput MIC Determination Method to Screen Uranium Resistant Microorganisms

The assessment of minimum inhibitory concentration (MIC) is a conventional technique used for the screening of microbial resistance against antibiotics, biocides, and contaminants such as heavy metals. However, as part of our ongoing work, we have observed biases associated with using traditional liquid MIC method to screen microbial heavy metal resistance, including both bacterial and fungal strains. Specifically, the addition of uranium into synthetic media causes immediate precipitation prior to the initiation of microbial growth, thus hampering the optical density measurements, and the obtained MIC values are thus flawed and inaccurate. To address this discrepancy, we report the optimization and development of a serial-dilution-based MIC method conducted on solid growth media supplemented with uranium, which is more accurate, relative to the testing of MICs performed in liquid cultures. Notably, we report on the efficacy of this method to screen not only bacteria that are resistant to uranium but also demonstrate the successful application to yeast and fungal isolates, for their ability to resist uranium, is more accurate and sensitive relative to the liquid method. We believe that this newly developed method to screen heavy metal resistance, such as uranium, is far superior to the existing liquid MIC method and propose replacing the liquid assay with the solid plate MIC reported herein.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2025

Antimicrobial activity of peptoids against Metallo-β-lactamase-producing Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa , and other WHO priority pathogens, including Candida auris

Abstract Aims The World Health Organization has identified ESKAPE bacteria and Candida auris as priority pathogens, emphasizing an urgent need for novel antimicrobials to combat them. This study aimed to explore the therapeutic potential of antimicrobial peptidomimetics, specifically peptoids with sequence-specific N-substituted glycines, against ESKAPEE pathogens, including metallo-β-lactamase (MBL) producers, as well as C. auris strains. Methods and results This study evaluated activity of the peptoids against the multidrug-resistant priority pathogens. The peptoid TM8 (with an N-decyl alkyl chain) demonstrated a geometric mean minimum inhibitory concentration (MIC) of 7.8 μg ml−1 against MBL-producing bacteria, and 5.5 μg ml−1 against C. auris. TM8 showed synergy with ciprofloxacin, enhancing its effectiveness 4-fold against NDM-1-producing Klebsiella pneumoniae. No antagonism was seen when TM8 was used with either conventional antibiotics or antifungals. Peptoids that had therapeutic indices below 3 were generally more hydrophobic, due to either alkyl chains or bromine. Scanning electron microscopy and live-dead staining assay on peptoid-treated C. auris confirmed morphological changes and killing activity, respectively. Furthermore, the peptoid could effectively inhibit biofilm formation by C. auris. Conclusion Peptoids demonstrated antibacterial activity against ESKAPEE, particularly against MBL-producing Gram-negative bacteria. Additionally, they exhibited antifungal and anti-biofilm activities against C. auris strains.

Biotechnology & Applied Microbiology↗
DOE OSTI2025

Resistance to oxyimino-cephalosporins conferred by an alternative mechanism of hydrolysis by the Acinetobacter -derived cephalosporinase-33 (ADC-33), a class C β-lactamase present in carbapenem-resistant Acinetobacter baumannii (CR Ab )

ABSTRACT Antimicrobial resistance inAcinetobacter baumanniiis partly mediated by chromosomal class C β-lactamases, theAcinetobacter-derived cephalosporinases (ADCs). Recently, a growing number of emerging variants were described, expanding this threat. Consistent with other β-lactamases, one of the main areas of variance exists in the Ω-loop region near the site of cephalosporin binding. Interestingly, a common alanine duplication (Adup) is found in this region. Herein, we studied specific Adup variants expressed in a uniformEscherichia coligenetic background that demonstrated high-level resistance to multiple oxyimino-cephalosporins. For ceftolozane and ceftazidime, the Adup ADCs significantly increased levels of resistance (minimum inhibitory concentration [MIC] ≥ 512 µg/mL and MIC ≥ 1,024 µg/mL, respectively). These observations were consistent with the increasedk cat /K M for ceftazidime. For cefiderocol, three Adup variants exhibited increased MICs and increasedk cat /K M for this compound. Timed electrospray ionization mass spectrometry demonstrated stable cephalosporin:ADC adducts with ADC-30 (non-Adup), but not with ADC-33 (Adup), consistent with turnover. The X-ray crystal structure of Adup variant ADC-33 in complex with ceftazidime was determined (1.57 Å resolution) and suggests that increased turnover is facilitated by conformational changes (shift in Tyr221 and orientation of the oxyimino portion of the R1 side chain) and repositioning of water in the active site. These changes appear to favor substrate-assisted catalysis as an alternative mechanism to base-assisted catalysis. These studies also provide unprecedented insight into the mechanism underlying oxyimino-cephalosporin hydrolysis by expanded-spectrum ADC β-lactamases and possibly other class C β-lactamases, which is of critical importance to future drug design. IMPORTANCE The characterization of emergingAcinetobacter-derived cephalosporinase (ADC) variants is necessary to understand the increasing resistance to β-lactam antibiotics inAcinetobacterspp. In this study, cefiderocol retains effectiveness against ADC variants with and without an Ω-loop alanine duplication (Adup). However, the presence of the Adup appears to introduce loop flexibility and structural alterations resulting in increased resistance and steady-state turnover of larger cephalosporins. Further characterization provides unprecedented insight into the mechanism of cephalosporin hydrolysis by ADC β-lactamases and supports a concomitant increase in ADC structural flexibility and cephalosporin affinity that leads to more efficient hydrolysis. In addition, the crystal structure of ADC-33 in complex with ceftazidime is consistent with a substrate-assisted catalysis mechanism. The structural differences in the ADC-33 active site leading to ceftazidime catalysis provide a better understanding of β-lactamase Adup variants and open important opportunities for future drug design and development.

Microbiology↗
DOE OSTI2020

Antibacterial activity of iron oxide, iron nitride, and tobramycin conjugated nanoparticles against Pseudomonas aeruginosa biofilms

Novel methods are necessary to reduce morbidity and mortality of patients suffering from infections with Pseudomonas aeruginosa. Being the most common infectious species of the Pseudomonas genus, P. aeruginosa is the primary Gram-negative etiology responsible for nosocomial infections. Due to the ubiquity and high adaptability of this species, an effective universal treatment method for P. aeruginosa infection still eludes investigators, despite the extensive research in this area. Results We report bacterial inhibition by iron-oxide (nominally magnetite) nanoparticles (NPs) alone, having a mean hydrodynamic diameter of ~ 16 nm, as well as alginate-capped iron-oxide NPs. Alginate capping increased the average hydrodynamic diameter to ~ 230 nm. We also investigated alginate-capped iron-oxide NP-drug conjugates, with a practically unchanged hydrodynamic diameter of ~ 232 nm. Susceptibility and minimum inhibitory concentration (MIC) of the NPs, NP-tobramycin conjugates, and tobramycin alone were determined in the PAO1 bacterial colonies. Investigations into susceptibility using the disk diffusion method were done after 3 days of biofilm growth and after 60 days of growth. MIC of all compounds of interest was determined after 60-days of growth, to ensure thorough establishment of biofilm colonies. Conclusions Positive inhibition is reported for uncapped and alginate-capped iron-oxide NPs, and the corresponding MICs are presented. We report zero susceptibility to iron-oxide NPs capped with polyethylene glycol, suggesting that the capping agent plays a major role in enabling bactericidal ability in of the nanocomposite. Our findings suggest that the alginate-coated nanocomposites investigated in this study have the potential to overcome the bacterial biofilm barrier. Magnetic field application increases the action, likely via enhanced diffusion of the iron-oxide NPs and NP-drug conjugates through mucin and alginate barriers, which are characteristic of cystic-fibrosis respiratory infections. We demonstrate that iron-oxide NPs coated with alginate, as well as alginate-coated magnetite–tobramycin conjugates inhibit P. aeruginosa growth and biofilm formation in established colonies. We have also determined that susceptibility to tobramycin decreases for longer culture times. However, susceptibility to the iron-oxide NP compounds did not demonstrate any comparable decrease with increasing culture time. These findings imply that iron-oxide NPs are promising lower-cost alternatives to silver NPs in antibacterial coatings, solutions, and drugs, as well as other applications in which microbial abolition or infestation prevention is sought.

Biotechnology & Applied Microbiology↗
DOE OSTI2024

In Vitro Antimicrobial Activity of Volatile Compounds from the Lichen Pseudevernia furfuracea (L.) Zopf. Against Multidrug-Resistant Bacteria and Fish Pathogens

Lichens are symbiotic organisms with unique secondary metabolism. Various metabolites from lichens have shown antimicrobial activity. Nevertheless, very few studies have investigated the antimicrobial potential of the volatile compounds they produce. This study investigates the chemical composition and antimicrobial properties of volatile compounds from Pseudevernia furfuracea collected in two regions of Morocco. Hydrodistillation was used to obtain volatile compounds from samples collected in the High Atlas and Middle Atlas. Gas chromatography–mass spectrometry (GC-MS) analysis identified phenolic cyclic compounds as the primary constituents, with atraric acid and chloroatranol being the most abundant. Additionally, eight compounds were detected in lichens for the first time. The antimicrobial activity of these compounds was assessed using disc diffusion and broth microdilution methods. Both samples demonstrated significant antimicrobial effects against multidrug-resistant human bacteria, reference microorganisms, fish pathogens, and Candida albicans, with minimum inhibitory concentrations (MICs) ranging from 1000 µg/mL to 31.25 µg/mL. This study provides the first report on the volatile compounds from Pseudevernia furfuracea and their antimicrobial effects, particularly against fish pathogens, suggesting their potential as novel antimicrobial agents for human and veterinary use. Further research is warranted to explore these findings in more detail.

Essadki, Yasser (ORCID:0009000648460075)↗
DOE OSTI2020

Discovery of a Natural Product That Binds to the Mycobacterium tuberculosis Protein Rv1466 Using Native Mass Spectrometry

Elucidation of the mechanism of action of compounds with cellular bioactivity is important for progressing compounds into future drug development. In recent years, phenotype-based drug discovery has become the dominant approach to drug discovery over target-based drug discovery, which relies on the knowledge of a specific drug target of a disease. Still, when targeting an infectious disease via a high throughput phenotypic assay it is highly advantageous to identifying the compound’s cellular activity. A fraction derived from the plant Polyalthia sp. showed activity against Mycobacterium tuberculosis at 62.5 μge/μL. A known compound, altholactone, was identified from this fraction that showed activity towards M. tuberculosis at an minimum inhibitory concentration (MIC) of 64 μM. Retrospective analysis of a target-based screen against a TB proteome panel using native mass spectrometry established that the active fraction was bound to the mycobacterial protein Rv1466 with an estimated pseudo-Kd of 42.0 ± 6.1 µM. Our findings established Rv1466 as the potential molecular target of altholactone, which is responsible for the observed in vivo toxicity towards M. tuberculosis .

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

The activity of antimicrobial peptoids against multidrug-resistant ocular pathogens

Background: Ocular infections caused by antibiotic-resistant pathogens can result in partial or complete vision loss. The development of pan-resistant microbial strains poses a significant challenge for clinicians as there are limited antimicrobial options available. Synthetic peptoids, which are sequence-specific oligo-N-substituted glycines, offer potential as alternative antimicrobial agents to target multidrug-resistant bacteria. Methods: The antimicrobial activity of synthesised peptoids against multidrug-resistant (MDR) ocular pathogens was evaluated using the microbroth dilution method. Hemolytic propensity was assessed using mammalian erythrocytes. Peptoids were also incubated with proteolytic enzymes, after which their minimum inhibitory activity against bacteria was re-evaluated. Results: Several alkylated and brominated peptoids showed good inhibitory activity against multidrug-resistant Pseudomonas aeruginosa strains at concentrations of ≤15 μg mL -1 (≤12 µM). Similarly, most brominated compounds inhibited the growth of methicillin-resistant Staphylococcus aureus at 1.9 to 15 μg mL -1 (12 µM). The N-terminally alkylated peptoids caused less toxicity to erythrocytes. The peptoid denoted as TM5 had a high therapeutic index, being non-toxic to either erythrocytes or corneal epithelial cells, even at 15 to 22 times its MIC. Additionally, the peptoids were resistant to protease activity. Conclusions: Peptoids studied here demonstrated potent activity against various multidrug-resistant ocular pathogens. Their properties make them promising candidates for controlling vision-related morbidity associated with eye infections by antibiotic-resistant strains.

60 APPLIED LIFE SCIENCES↗