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Arachidonic Acid Kills Staphylococcus aureus through a Lipid Peroxidation Mechanism.
Beavers WN, Monteith AJ, Amarnath V, Mernaugh RL, Roberts LJ, Chazin WJ, Davies SS, Skaar EP
(2019) mBio 10:
MeSH Terms: Animals, Anti-Bacterial Agents, Arachidonic Acid, Brain, Dose-Response Relationship, Drug, Drug Resistance, Bacterial, Female, Kidney, Lipid Peroxidation, Lipids, Mice, Mice, Inbred BALB C, Microbial Sensitivity Tests, Mutation, Neutrophils, Oxidative Stress, Reactive Oxygen Species, Spleen, Staphylococcal Infections, Staphylococcus aureus, Teichoic Acids
Show Abstract · Added March 11, 2020
infects every niche of the human host. In response to microbial infection, vertebrates have an arsenal of antimicrobial compounds that inhibit bacterial growth or kill bacterial cells. One class of antimicrobial compounds consists of polyunsaturated fatty acids, which are highly abundant in eukaryotes and encountered by at the host-pathogen interface. Arachidonic acid (AA) is one of the most abundant polyunsaturated fatty acids in vertebrates and is released in large amounts during the oxidative burst. Most of the released AA is converted to bioactive signaling molecules, but, independently of its role in inflammatory signaling, AA is toxic to Here, we report that AA kills through a lipid peroxidation mechanism whereby AA is oxidized to reactive electrophiles that modify macromolecules, eliciting toxicity. This process is rescued by cotreatment with antioxidants as well as in a strain genetically inactivated for (USA300 mutant) that produces lower levels of reactive oxygen species. However, resistance to AA stress in the USA300 mutant comes at a cost, making the mutant more susceptible to β-lactam antibiotics and attenuated for pathogenesis in a murine infection model compared to the parental methicillin-resistant (MRSA) strain, indicating that resistance to AA toxicity increases susceptibility to other stressors encountered during infection. This report defines the mechanism by which AA is toxic to and identifies lipid peroxidation as a pathway that can be modulated for the development of future therapeutics to treat infections. Despite the ability of the human immune system to generate a plethora of molecules to control infections, is among the pathogens with the greatest impact on human health. One class of host molecules toxic to consists of polyunsaturated fatty acids. Here, we investigated the antibacterial properties of arachidonic acid, one of the most abundant polyunsaturated fatty acids in humans, and discovered that the mechanism of toxicity against proceeds through lipid peroxidation. A better understanding of the molecular mechanisms by which the immune system kills , and by which avoids host killing, will enable the optimal design of therapeutics that complement the ability of the vertebrate immune response to eliminate infections.
Copyright © 2019 Beavers et al.
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21 MeSH Terms
Helicobacter pylori antimicrobial resistance and antibiotic consumption in the low-resource Central America setting.
Ortiz V, Estevez-Ordonez D, Montalvan-Sanchez E, Urrutia-Argueta S, Israel D, Krishna US, Romero-Gallo J, Wilson KT, Peek RM, Dominguez R, Morgan DR
(2019) Helicobacter 24: e12595
MeSH Terms: Adult, Aged, Amoxicillin, Anti-Bacterial Agents, Central America, Drug Resistance, Bacterial, Female, Helicobacter Infections, Helicobacter pylori, Humans, Levofloxacin, Male, Microbial Sensitivity Tests, Middle Aged
Show Abstract · Added May 23, 2019
BACKGROUND - Antimicrobial resistance is a global public health problem, particularly in low- and middle-income countries (LMICs), where antibiotics are often obtained without a prescription. H. pylori antimicrobial resistance patterns are informative for patient care and gastric cancer prevention programs, have been shown to correlate with general antimicrobial consumption, and may guide antimicrobial stewardship programs in LMICs. We report H. pylori resistance and antimicrobial utilization patterns for western Honduras, representative of rural Central America.
METHODS - In the context of the western Honduras gastric cancer epidemiology initiative, gastric biopsies from 189 patients were studied for culture and resistance patterns. Antimicrobial utilization was investigated for common H. pylori treatment regimens from regional public (7 antimicrobials) and national private (4 antimicrobials) data, analyzed in accordance with WHO anatomical therapeutic chemical defined daily doses (DDD) method and expressed as DDD/1000 inhabitants per day (DID) and per year (DIY).
RESULTS - H. pylori was successfully cultured from 116 patients (56% males, mean age: 54), and nearly all strains were cagA+ and vacAs1m1+ positive (99% and 90.4%, respectively). Unexpectedly, high resistance was noted for levofloxacin (20.9%) and amoxicillin (10.7%), while metronidazole (67.9%) and clarithromycin (11.2%) were similar to data from Latin America. Significant associations with age, gender, or histology were not noted, with the exception of levofloxacin (28%, P = 0.01) in those with histology limited to non-atrophic gastritis. Total antimicrobial usage in western Honduras of amoxicillin (17.3 DID) and the quinolones had the highest relative utilizations compared with other representative nations.
CONCLUSIONS - We observed significant H. pylori resistance to amoxicillin and levofloxacin in the context of high community antimicrobial utilization. This has implications in Central America for H. pylori treatment guidelines as well as antimicrobial stewardship programs.
© 2019 John Wiley & Sons Ltd.
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Apotransferrin in Combination with Ciprofloxacin Slows Bacterial Replication, Prevents Resistance Amplification, and Increases Antimicrobial Regimen Effect.
Ambrose PG, VanScoy BD, Luna BM, Yan J, Ulhaq A, Nielsen TB, Rudin S, Hujer K, Bonomo RA, Actis L, Skaar E, Spellberg B
(2019) Antimicrob Agents Chemother 63:
MeSH Terms: Anti-Bacterial Agents, Apoproteins, Ciprofloxacin, Fluoroquinolones, Klebsiella, Microbial Sensitivity Tests, Transferrin
Show Abstract · Added April 7, 2019
There has been renewed interest in combining traditional small-molecule antimicrobial agents with nontraditional therapies to potentiate antimicrobial effects. Apotransferrin, which decreases iron availability to microbes, is one such approach. We conducted a 48-h one-compartment infection model to explore the impact of apotransferrin on the bactericidal activity of ciprofloxacin. The challenge panel included four isolates with ciprofloxacin MIC values ranging from 0.08 to 32 mg/liter. Each challenge isolate was subjected to an ineffective ciprofloxacin monotherapy exposure (free-drug area under the concentration-time curve over 24 h divided by the MIC [AUC/MIC ratio] ranging from 0.19 to 96.6) with and without apotransferrin. As expected, the no-treatment and apotransferrin control arms showed unaltered prototypical logarithmic bacterial growth. We identified relationships between exposure and change in bacterial density for ciprofloxacin alone ( = 0.64) and ciprofloxacin in combination with apotransferrin ( = 0.84). Addition of apotransferrin to ciprofloxacin enabled a remarkable reduction in bacterial density across a wide range of ciprofloxacin exposures. For instance, at a ciprofloxacin AUC/MIC ratio of 20, ciprofloxacin monotherapy resulted in nearly 2 log CFU increase in bacterial density, while the combination of apotransferrin and ciprofloxacin resulted in 2 log CFU reduction in bacterial density. Furthermore, addition of apotransferrin significantly reduced the emergence of ciprofloxacin-resistant subpopulations compared to monotherapy. These data demonstrate that decreasing the rate of bacterial replication with apotransferrin in combination with antimicrobial therapy represents an opportunity to increase the magnitude of the bactericidal effect and to suppress the growth rate of drug-resistant subpopulations.
Copyright © 2019 American Society for Microbiology.
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7 MeSH Terms
Amycomicin is a potent and specific antibiotic discovered with a targeted interaction screen.
Pishchany G, Mevers E, Ndousse-Fetter S, Horvath DJ, Paludo CR, Silva-Junior EA, Koren S, Skaar EP, Clardy J, Kolter R
(2018) Proc Natl Acad Sci U S A 115: 10124-10129
MeSH Terms: Anthraquinones, Anti-Bacterial Agents, DNA, Bacterial, DNA, Ribosomal, Microbial Sensitivity Tests, RNA, Ribosomal, 16S, Streptomyces coelicolor
Show Abstract · Added April 7, 2019
The rapid emergence of antibiotic-resistant pathogenic bacteria has accelerated the search for new antibiotics. Many clinically used antibacterials were discovered through culturing a single microbial species under nutrient-rich conditions, but in the environment, bacteria constantly encounter poor nutrient conditions and interact with neighboring microbial species. In an effort to recapitulate this environment, we generated a nine-strain actinomycete community and used 16S rDNA sequencing to deconvolute the stochastic production of antimicrobial activity that was not observed from any of the axenic cultures. We subsequently simplified the community to just two strains and identified sp. AA4 as the producing strain and M145 as an inducing strain. Bioassay-guided isolation identified amycomicin (AMY), a highly modified fatty acid containing an epoxide isonitrile warhead as a potent and specific inhibitor of Amycomicin targets an essential enzyme (FabH) in fatty acid biosynthesis and reduces infection in a mouse skin-infection model. The discovery of AMY demonstrates the utility of screening complex communities against specific targets to discover small-molecule antibiotics.
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Structure and Function of the Transmembrane Domain of NsaS, an Antibiotic Sensing Histidine Kinase in Staphylococcus aureus.
Bhate MP, Lemmin T, Kuenze G, Mensa B, Ganguly S, Peters JM, Schmidt N, Pelton JG, Gross CA, Meiler J, DeGrado WF
(2018) J Am Chem Soc 140: 7471-7485
MeSH Terms: Anti-Bacterial Agents, Bacitracin, Bacterial Proteins, Gene Knockout Techniques, Histidine Kinase, Hydrophobic and Hydrophilic Interactions, Magnetic Resonance Spectroscopy, Membrane Proteins, Microbial Sensitivity Tests, Molecular Dynamics Simulation, Nisin, Protein Conformation, alpha-Helical, Protein Domains, Staphylococcus aureus
Show Abstract · Added March 21, 2020
NsaS is one of four intramembrane histidine kinases (HKs) in Staphylococcus aureus that mediate the pathogen's response to membrane active antimicrobials and human innate immunity. We describe the first integrative structural study of NsaS using a combination of solution state NMR spectroscopy, chemical-cross-linking, molecular modeling and dynamics. Three key structural features emerge: First, NsaS has a short N-terminal amphiphilic helix that anchors its transmembrane (TM) bundle into the inner leaflet of the membrane such that it might sense neighboring proteins or membrane deformations. Second, the transmembrane domain of NsaS is a 4-helix bundle with significant dynamics and structural deformations at the membrane interface. Third, the intracellular linker connecting the TM domain to the cytoplasmic catalytic domains of NsaS is a marginally stable helical dimer, with one state likely to be a coiled-coil. Data from chemical shifts, heteronuclear NOE, H/D exchange measurements and molecular modeling suggest that this linker might adopt different conformations during antibiotic induced signaling.
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Utility of Blood Culture Among Children Hospitalized With Community-Acquired Pneumonia.
Neuman MI, Hall M, Lipsett SC, Hersh AL, Williams DJ, Gerber JS, Brogan TV, Blaschke AJ, Grijalva CG, Parikh K, Ambroggio L, Shah SS, Pediatric Research in Inpatient Settings Network
(2017) Pediatrics 140:
MeSH Terms: Adolescent, Anti-Bacterial Agents, Bacteremia, Bacteria, Blood Culture, Child, Child, Preschool, Community-Acquired Infections, Cross-Sectional Studies, Female, Hospitalization, Humans, Infant, Male, Microbial Sensitivity Tests, Penicillins, Pneumonia, Bacterial, Retrospective Studies
Show Abstract · Added July 27, 2018
BACKGROUND AND OBJECTIVES - National guidelines recommend blood cultures for children hospitalized with presumed bacterial community-acquired pneumonia (CAP) that is moderate or severe. We sought to determine the prevalence of bacteremia and characterize the microbiology and penicillin-susceptibility patterns of positive blood culture results among children hospitalized with CAP.
METHODS - We conducted a cross-sectional study of children hospitalized with CAP in 6 children's hospitals from 2007 to 2011. We included children 3 months to 18 years of age with discharge diagnosis codes for CAP using a previously validated algorithm. We excluded children with complex chronic conditions. We reviewed microbiologic data and classified positive blood culture detections as pathogens or contaminants. Antibiotic-susceptibility patterns were assessed for all pathogens.
RESULTS - A total of 7509 children hospitalized with CAP were included over the 5-year study period. Overall, 34% of the children hospitalized with CAP had a blood culture performed; 65 (2.5% of patients with blood cultures; 95% confidence interval [CI]: 2.0%-3.2%) grew a pathogen. accounted for 78% of all detected pathogens. Among detected pathogens, 50 (82%) were susceptible to penicillin. Eleven children demonstrated growth of an organism nonsusceptible to penicillin, representing 0.43% (95% CI: 0.23%-0.77%) of children with blood cultures obtained and 0.15% (95% CI: 0.08%-0.26%) of all children hospitalized with CAP.
CONCLUSIONS - Among children without comorbidities hospitalized with CAP in a non-ICU setting, the rate of bacteremia was low, and isolated pathogens were usually susceptible to penicillin. Blood cultures may not be needed for most children hospitalized with CAP.
Copyright © 2017 by the American Academy of Pediatrics.
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Magnetic Extraction of Acinetobacter baumannii Using Colistin-Functionalized γ-FeO/Au Core/Shell Composite Nanoclusters.
Bell CS, Mejías R, Miller SE, Greer JM, McClain MS, Cover TL, Giorgio TD
(2017) ACS Appl Mater Interfaces 9: 26719-26730
MeSH Terms: Acinetobacter Infections, Acinetobacter baumannii, Anti-Bacterial Agents, Colistin, Drug Resistance, Multiple, Bacterial, Ferric Compounds, Humans, Microbial Sensitivity Tests
Show Abstract · Added March 21, 2018
Acinetobacter baumannii is a Gram-negative bacterium of increasing concern due to its virulence and persistence in combat and healthcare environments. The incidence of both community-acquired and nosocomial A. baumannii infections is on the rise in foreign and domestic healthcare facilities. Treatment options are limited due to the acquisition of multidrug resistance to the few effective antibiotics. Currently, the most effective pharmaceutically based treatment for multidrug-resistant A. baumannii infections is the antibiotic colistin (polymyxin E). To minimize side effects associated with administration of colistin or other toxic antimicrobial agents, we propose the development of a nanotechnology-mediated treatment strategy. In this design-based effort, colistin-functionalized multilayered, inorganic, magnetoplasmonic nanoconstructs were fabricated to bind to the surface of A. baumannii. This result, for the first time, demonstrates a robust, pharmaceutical-based motif for high affinity, composite nanoparticulates targeting the A. baumannii surface. The antibiotic-activated nanomaterials demonstrated cytocompatibility with human cells and no acute bacterial toxicity at nanoparticle to bacterial concentrations <10 000:1. The magnetomotive characteristics of the nanomaterial enabled magnetic extraction of the bacteria. In a macroscale environment, maximal separation efficiencies exceeding 38% were achieved. This result demonstrates the potential for implementation of this technology into micro- or mesofluidic-based separation environments to enhance extraction efficiencies. The future development of such a mesofluidic-based, nanotechnology-mediated platform is potentially suitable for adjuvant therapies to assist in the treatment of sepsis.
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Impact of an Integrated Antibiotic Allergy Testing Program on Antimicrobial Stewardship: A Multicenter Evaluation.
Trubiano JA, Thursky KA, Stewardson AJ, Urbancic K, Worth LJ, Jackson C, Stevenson W, Sutherland M, Slavin MA, Grayson ML, Phillips EJ
(2017) Clin Infect Dis 65: 166-174
MeSH Terms: Aged, Anti-Bacterial Agents, Antimicrobial Stewardship, Australia, Drug Hypersensitivity, Drug-Related Side Effects and Adverse Reactions, Female, Hospitals, Humans, Inappropriate Prescribing, Male, Microbial Sensitivity Tests, Middle Aged, Penicillins, Skin Tests
Show Abstract · Added March 30, 2020
Background - Despite the high prevalence of patient-reported antibiotic allergy (so-called antibiotic allergy labels [AALs]) and their impact on antibiotic prescribing, incorporation of antibiotic allergy testing (AAT) into antimicrobial stewardship (AMS) programs (AAT-AMS) is not widespread. We aimed to evaluate the impact of an AAT-AMS program on AAL prevalence, antibiotic usage, and appropriateness of prescribing.
Methods - AAT-AMS was implemented at two large Australian hospitals during a 14-month period beginning May 2015. Baseline demographics, AAL history, age-adjusted Charlson comorbidity index, infection history, and antibiotic usage for 12 months prior to testing (pre-AAT-AMS) and 3 months following testing (post-AAT-AMS) were recorded for each participant. Study outcomes included the proportion of patients who were "de-labeled" of their AAL, spectrum of antibiotic courses pre- and post-AAT-AMS, and antibiotic appropriateness (using standard definitions).
Results - From the 118 antibiotic allergy-tested patients, 226 AALs were reported (mean, 1.91/patient), with 53.6% involving 1 or more penicillin class drug. AAT-AMS allowed AAL de-labeling in 98 (83%) patients-56% (55/98) with all AALs removed. Post-AAT, prescribing of narrow-spectrum penicillins was more likely (adjusted odds ratio [aOR], 2.81, 95% confidence interval [CI], 1.45-5.42), as was narrow-spectrum β-lactams (aOR, 3.54; 95% CI, 1.98-6.33), and appropriate antibiotics (aOR, 12.27; 95% CI, 5.00-30.09); and less likely for restricted antibiotics (aOR, 0.16; 95% CI, .09-.29), after adjusting for indication, Charlson comorbidity index, and care setting.
Conclusions - An integrated AAT-AMS program was effective in both de-labeling of AALs and promotion of improved antibiotic usage and appropriateness, supporting the routine incorporation of AAT into AMS programs.
© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.
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Isoniazid-monoresistant tuberculosis is associated with poor treatment outcomes in Durban, South Africa.
van der Heijden YF, Karim F, Mufamadi G, Zako L, Chinappa T, Shepherd BE, Maruri F, Moosa MS, Sterling TR, Pym AS
(2017) Int J Tuberc Lung Dis 21: 670-676
MeSH Terms: Adult, Antitubercular Agents, Drug Resistance, Bacterial, Female, HIV Infections, Humans, Isoniazid, Logistic Models, Longitudinal Studies, Male, Microbial Sensitivity Tests, Mycobacterium tuberculosis, Retrospective Studies, South Africa, Treatment Failure, Treatment Outcome, Tuberculosis
Show Abstract · Added March 14, 2018
SETTING - A large tuberculosis (TB) clinic in Durban, South Africa.
OBJECTIVE - To determine the association between isoniazid (INH) monoresistant TB and treatment outcomes.
DESIGN - We performed a retrospective longitudinal study of patients seen from 2000 to 2012 to compare episodes of INH-monoresistant TB with those of drug-susceptible TB using logistic regression with robust standard errors. INH-monoresistant TB was treated with modified regimens.
RESULTS - Among 18 058 TB patients, there were 19 979 TB episodes for which drug susceptibility testing was performed. Of these, 557 were INH-monoresistant and 16 311 were drug-susceptible. Loss to follow-up, transfer, and human immunodeficiency virus (HIV) co-infection (41% had known HIV status) were similar between groups. INH-monoresistant episodes were more likely to result in treatment failure (4.1% vs. 0.6%, P < 0.001) and death (3.2% vs. 1.8%, P = 0.01) than drug-susceptible episodes. After adjustment for age, sex, race, retreatment status, and disease site, INH-monoresistant episodes were more likely to have resulted in treatment failure (OR 6.84, 95%CI 4.29-10.89, P < 0.001) and death (OR 1.81, 95%CI 1.11-2.95, P = 0.02).
CONCLUSION - INH monoresistance was associated with worse clinical outcomes than drug-susceptible TB. Our findings support the need for rapid diagnostic tests for INH resistance and improved treatment regimens for INH-monoresistant TB.
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Structural analyses of sterol 14α-demethylase complexed with azole drugs address the molecular basis of azole-mediated inhibition of fungal sterol biosynthesis.
Hargrove TY, Friggeri L, Wawrzak Z, Qi A, Hoekstra WJ, Schotzinger RJ, York JD, Guengerich FP, Lepesheva GI
(2017) J Biol Chem 292: 6728-6743
MeSH Terms: Animals, Antifungal Agents, Azoles, Candida albicans, Crystallization, Fungal Proteins, Heme, Humans, Kinetics, Ligands, Microbial Sensitivity Tests, Protein Binding, Protein Conformation, Protons, Rats, Sterol 14-Demethylase, Sterols
Show Abstract · Added March 14, 2018
With some advances in modern medicine (such as cancer chemotherapy, broad exposure to antibiotics, and immunosuppression), the incidence of opportunistic fungal pathogens such as has increased. Cases of drug resistance among these pathogens have become more frequent, requiring the development of new drugs and a better understanding of the targeted enzymes. Sterol 14α-demethylase (CYP51) is a cytochrome P450 enzyme required for biosynthesis of sterols in eukaryotic cells and is the major target of clinical drugs for managing fungal pathogens, but some of the CYP51 key features important for rational drug design have remained obscure. We report the catalytic properties, ligand-binding profiles, and inhibition of enzymatic activity of CYP51 by clinical antifungal drugs that are used systemically (fluconazole, voriconazole, ketoconazole, itraconazole, and posaconazole) and topically (miconazole and clotrimazole) and by a tetrazole-based drug candidate, VT-1161 (oteseconazole: ()-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1-tetrazol-1-yl)-1-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-ol). Among the compounds tested, the first-line drug fluconazole was the weakest inhibitor, whereas posaconazole and VT-1161 were the strongest CYP51 inhibitors. We determined the X-ray structures of CYP51 complexes with posaconazole and VT-1161, providing a molecular mechanism for the potencies of these drugs, including the activity of VT-1161 against and , pathogens that are intrinsically resistant to fluconazole. Our comparative structural analysis outlines phylum-specific CYP51 features that could direct future rational development of more efficient broad-spectrum antifungals.
© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
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