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Nonconventional Therapeutics against .
Grunenwald CM, Bennett MR, Skaar EP
(2018) Microbiol Spectr 6:
MeSH Terms: Anti-Bacterial Agents, Antibodies, Bacterial, Bacteriophages, Biofilms, Drug Discovery, Drug Resistance, Multiple, Bacterial, Humans, Phage Therapy, Photochemotherapy, Quorum Sensing, Staphylococcal Infections, Staphylococcus aureus, Virulence, Virulence Factors
Show Abstract · Added April 7, 2019
is one of the most important human pathogens that is responsible for a variety of diseases ranging from skin and soft tissue infections to endocarditis and sepsis. In recent decades, the treatment of staphylococcal infections has become increasingly difficult as the prevalence of multi-drug resistant strains continues to rise. With increasing mortality rates and medical costs associated with drug resistant strains, there is an urgent need for alternative therapeutic options. Many innovative strategies for alternative drug development are being pursued, including disruption of biofilms, inhibition of virulence factor production, bacteriophage-derived antimicrobials, anti-staphylococcal vaccines, and light-based therapies. While many compounds and methods still need further study to determine their feasibility, some are quickly approaching clinical application and may be available in the near future.
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Distinct mucosal microbial communities in infants with surgical necrotizing enterocolitis correlate with age and antibiotic exposure.
Romano-Keeler J, Shilts MH, Tovchigrechko A, Wang C, Brucker RM, Moore DJ, Fonnesbeck C, Meng S, Correa H, Lovvorn HN, Tang YW, Hooper L, Bordenstein SR, Das SR, Weitkamp JH
(2018) PLoS One 13: e0206366
MeSH Terms: Age Factors, Anti-Bacterial Agents, Biodiversity, Enterocolitis, Necrotizing, Female, Humans, Infant, Infant, Newborn, Intestinal Mucosa, Male, Microbiota, Pregnancy
Show Abstract · Added October 27, 2018
OBJECTIVE - Necrotizing enterocolitis (NEC) is the most common surgical emergency in preterm infants, and pathogenesis associates with changes in the fecal microbiome. As fecal samples incompletely represent microbial communities in intestinal mucosa, we sought to determine the NEC tissue-specific microbiome and assess its contribution to pathogenesis.
DESIGN - We amplified and sequenced the V1-V3 hypervariable region of the bacterial 16S rRNA gene extracted from intestinal tissue and corresponding fecal samples from 12 surgical patients with NEC and 14 surgical patients without NEC. Low quality and non-bacterial sequences were removed, and taxonomic assignment was made with the Ribosomal Database Project. Operational taxonomic units were clustered at 97%. We tested for differences between NEC and non-NEC samples in microbiome alpha- and beta-diversity and differential abundance of specific taxa between NEC and non-NEC samples. Additional analyses were performed to assess the contribution of other demographic and environmental confounding factors on the infant tissue and fecal microbiome.
RESULTS - The fecal and tissue microbial communities were different. NEC was associated with a distinct microbiome, which was characterized by low diversity, higher abundances of Staphylococcus and Clostridium_sensu_stricto, and lower abundances of Actinomyces and Corynebacterium. Infant age and vancomycin exposure correlated with shifts in the tissue microbiome.
CONCLUSION - The observed low diversity in NEC tissues suggests that NEC is associated with a bacterial bloom and a distinct mucosal bacterial community. The exact bacterial species that constitute the bloom varied by infant and were strongly influenced by age and exposure to vancomycin.
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12 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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The role of zinc and nutritional immunity in Clostridium difficile infection.
Zackular JP, Skaar EP
(2018) Gut Microbes 9: 469-476
MeSH Terms: Animals, Anti-Bacterial Agents, Clostridium Infections, Clostridium difficile, Disease Models, Animal, Gastrointestinal Microbiome, Humans, Immunity, Mice, Zinc
Show Abstract · Added March 15, 2018
Clostridium difficile in one of the most commonly reported nosocomial pathogens worldwide. Beyond antibiotic use, little is known about the host, microbiota, and environmental factors that contribute to susceptibility to and severity of C. difficile infection (CDI). We recently observed that in a mouse model of CDI, excess dietary zinc (Zn) alters the gut microbiota and decreases resistance to CDI. Moreover, we determined that high levels of Zn exacerbate C. difficile-associated disease and calprotectin-mediated Zn limitation is an essential host response to infection. In this addendum, we discuss how these findings add to our understanding of CDI and consider the potential implications of excess metal intake on the microbiota and infection.
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10 MeSH Terms
Selective killing of with pH-responsive helix-coil conformation transitionable antimicrobial polypeptides.
Xiong M, Bao Y, Xu X, Wang H, Han Z, Wang Z, Liu Y, Huang S, Song Z, Chen J, Peek RM, Yin L, Chen LF, Cheng J
(2017) Proc Natl Acad Sci U S A 114: 12675-12680
MeSH Terms: Amines, Animals, Anti-Bacterial Agents, Antimicrobial Cationic Peptides, Disease Models, Animal, Female, Glutamic Acid, Helicobacter Infections, Helicobacter pylori, Hydrogen-Ion Concentration, Mice, Mice, Inbred C57BL, Mice, Inbred ICR, Organ Specificity, Protein Conformation, alpha-Helical, Static Electricity, Stomach
Show Abstract · Added March 14, 2018
Current clinical treatment of infection, the main etiological factor in the development of gastritis, gastric ulcers, and gastric carcinoma, requires a combination of at least two antibiotics and one proton pump inhibitor. However, such triple therapy suffers from progressively decreased therapeutic efficacy due to the drug resistance and undesired killing of the commensal bacteria due to poor selectivity. Here, we report the development of antimicrobial polypeptide-based monotherapy, which can specifically kill under acidic pH in the stomach while inducing minimal toxicity to commensal bacteria under physiological pH. Specifically, we designed a class of pH-sensitive, helix-coil conformation transitionable antimicrobial polypeptides (HCT-AMPs) (PGA)--(PHLG-MHH), bearing randomly distributed negatively charged glutamic acid and positively charged poly(γ-6--(methyldihexylammonium)hexyl-l-glutamate) (PHLG-MHH) residues. The HCT-AMPs showed unappreciable toxicity at physiological pH when they adopted random coiled conformation. Under acidic condition in the stomach, they transformed to the helical structure and exhibited potent antibacterial activity against , including clinically isolated drug-resistant strains. After oral gavage, the HCT-AMPs afforded comparable killing efficacy to the triple-therapy approach while inducing minimal toxicity against normal tissues and commensal bacteria, in comparison with the remarkable killing of commensal bacteria by 65% and 86% in the ileal contents and feces, respectively, following triple therapy. This strategy renders an effective approach to specifically target and kill in the stomach while not harming the commensal bacteria/normal tissues.
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17 MeSH Terms
Effectiveness of β-Lactam Monotherapy vs Macrolide Combination Therapy for Children Hospitalized With Pneumonia.
Williams DJ, Edwards KM, Self WH, Zhu Y, Arnold SR, McCullers JA, Ampofo K, Pavia AT, Anderson EJ, Hicks LA, Bramley AM, Jain S, Grijalva CG
(2017) JAMA Pediatr 171: 1184-1191
MeSH Terms: Adolescent, Anti-Bacterial Agents, Child, Child, Preschool, Community-Acquired Infections, Drug Therapy, Combination, Hospitalization, Humans, Infant, Intensive Care Units, Pediatric, Length of Stay, Macrolides, Patient Readmission, Pneumonia, Bacterial, Propensity Score, Radiography, Treatment Outcome, beta-Lactams
Show Abstract · Added July 27, 2018
Importance - β-Lactam monotherapy and β-lactam plus macrolide combination therapy are both common empirical treatment strategies for children hospitalized with pneumonia, but few studies have evaluated the effectiveness of these 2 treatment approaches.
Objective - To compare the effectiveness of β-lactam monotherapy vs β-lactam plus macrolide combination therapy among a cohort of children hospitalized with pneumonia.
Design, Setting, and Participants - We analyzed data from the Etiology of Pneumonia in the Community Study, a multicenter, prospective, population-based study of community-acquired pneumonia hospitalizations conducted from January 1, 2010, to June 30, 2012, in 3 children's hospitals in Nashville, Tennessee; Memphis, Tennessee; and Salt Lake City, Utah. The study included all children (up to 18 years of age) who were hospitalized with radiographically confirmed pneumonia and who received β-lactam monotherapy or β-lactam plus macrolide combination therapy. Data analysis was completed in April 2017.
Main Outcomes and Measures - We defined the referent as β-lactam monotherapy, including exclusive use of an oral or parenteral second- or third-generation cephalosporin, penicillin, ampicillin, ampicillin-sulbactam, amoxicillin, or amoxicillin-clavulanate. Use of a β-lactam plus an oral or parenteral macrolide (azithromycin or clarithromycin) served as the comparison group. We modeled the association between these groups and patients' length of stay using multivariable Cox proportional hazards regression. Covariates included demographic, clinical, and radiographic variables. We further evaluated length of stay in a cohort matched by propensity to receive combination therapy. Logistic regression was used to evaluate secondary outcomes in the unmatched cohort, including intensive care admission, rehospitalizations, and self-reported recovery at follow-up.
Results - Our study included 1418 children (693 girls and 725 boys) with a median age of 27 months (interquartile range, 12-69 months). This cohort was 60.1% of the 2358 children enrolled in the Etiology of Pneumonia in the Community Study with radiographically confirmed pneumonia in the study period; 1019 (71.9%) received β-lactam monotherapy and 399 (28.1%) received β-lactam plus macrolide combination therapy. In the unmatched cohort, there was no statistically significant difference in length of hospital stay between children receiving β-lactam monotherapy and combination therapy (median, 55 vs 59 hours; adjusted hazard ratio, 0.87; 95% CI, 0.74-1.01). The propensity-matched cohort (n = 560, 39.5%) showed similar results. There were also no significant differences between treatment groups for the secondary outcomes.
Conclusions and Relevance - Empirical macrolide combination therapy conferred no benefit over β-lactam monotherapy for children hospitalized with community-acquired pneumonia. The results of this study elicit questions about the routine empirical use of macrolide combination therapy in this population.
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Erythematous plaques and papules on a premature infant.
Riemenschneider K, Redenius R, Reese J, Fine JD, Weitkamp JH, Tkaczyk E
(2017) J Am Acad Dermatol 76: e111-e112
MeSH Terms: Anti-Bacterial Agents, Apgar Score, Biopsy, Needle, Female, Follow-Up Studies, Gestational Age, Humans, Immunohistochemistry, Impetigo, Infant, Newborn, Infant, Premature, Male, Pregnancy, Pregnancy Complications, Infectious, Respiratory Distress Syndrome, Newborn, Streptococcal Infections, Treatment Outcome
Show Abstract · Added March 31, 2018
A 2240 gram boy was born at 33.2 weeks gestation with nonblanching, deeply erythematous plaques and papules on the back, flanks, and scalp (Figure 1). His mother was GBS positive and on antibiotic suppression for prior cutaneous MRSA and urinary tract infections. Intrapartum intravenous Penicillin G was administered, and the amniotic sac was artificially ruptured 4 hours prior to delivery to facilitate labor. The delivery was uncomplicated without concern for chorioamnionitis, but the patient initially required CPAP for respiratory distress with 1-minute and 5-minute Apgar scores of 7 and 8, respectively. A skin punch biopsy is shown (Figure 2).
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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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Use of a neutralizing antibody helps identify structural features critical for binding of toxin TcdA to the host cell surface.
Kroh HK, Chandrasekaran R, Rosenthal K, Woods R, Jin X, Ohi MD, Nyborg AC, Rainey GJ, Warrener P, Spiller BW, Lacy DB
(2017) J Biol Chem 292: 14401-14412
MeSH Terms: Amino Acid Sequence, Anti-Bacterial Agents, Antibodies, Monoclonal, Humanized, Antibodies, Neutralizing, Bacterial Proteins, Bacterial Toxins, Binding Sites, Antibody, Caco-2 Cells, Clostridium difficile, Conserved Sequence, Crystallography, X-Ray, Enterocytes, Enterotoxins, Epitope Mapping, Glucosyltransferases, Humans, Immunoglobulin Fab Fragments, Models, Molecular, Peptide Fragments, Protein Conformation, Protein Interaction Domains and Motifs, Recombinant Proteins, Repetitive Sequences, Amino Acid
Show Abstract · Added March 15, 2018
is a clinically significant pathogen that causes mild-to-severe (and often recurrent) colon infections. Disease symptoms stem from the activities of two large, multidomain toxins known as TcdA and TcdB. The toxins can bind, enter, and perturb host cell function through a multistep mechanism of receptor binding, endocytosis, pore formation, autoproteolysis, and glucosyltransferase-mediated modification of host substrates. Monoclonal antibodies that neutralize toxin activity provide a survival benefit in preclinical animal models and prevent recurrent infections in human clinical trials. However, the molecular mechanisms involved in these neutralizing activities are unclear. To this end, we performed structural studies on a neutralizing monoclonal antibody, PA50, a humanized mAb with both potent and broad-spectrum neutralizing activity, in complex with TcdA. Electron microscopy imaging and multiangle light-scattering analysis revealed that PA50 binds multiple sites on the TcdA C-terminal combined repetitive oligopeptides (CROPs) domain. A crystal structure of two PA50 Fabs bound to a segment of the TcdA CROPs helped define a conserved epitope that is distinct from previously identified carbohydrate-binding sites. Binding of TcdA to the host cell surface was directly blocked by either PA50 mAb or Fab and suggested that receptor blockade is the mechanism by which PA50 neutralizes TcdA. These findings highlight the importance of the CROPs C terminus in cell-surface binding and a role for neutralizing antibodies in defining structural features critical to a pathogen's mechanism of action. We conclude that PA50 protects host cells by blocking the binding of TcdA to cell surfaces.
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23 MeSH Terms
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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8 MeSH Terms