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Results: 1 to 10 of 38

Publication Record


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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MeSH Terms
Characterization and development of SAPP as a specific peptidic inhibitor that targets Porphyromonas gingivalis.
Ho MH, Lamont RJ, Chazin WJ, Chen H, Young DF, Kumar P, Xie H
(2018) Mol Oral Microbiol 33: 430-439
MeSH Terms: Adhesins, Bacterial, Bacterial Adhesion, Biofilms, Cell Membrane, Cysteine Endopeptidases, Dental Plaque, Fibroblasts, Gingipain Cysteine Endopeptidases, Humans, Peptides, Periodontitis, Porphyromonas gingivalis, Virulence
Show Abstract · Added March 26, 2019
Porphyromonas gingivalis is a keystone bacterium in the oral microbial communities that elicits a dysbiosis between the microbiota and the host. Therefore, inhibition of this organism in dental plaques has been one of the strategies for preventing and treating chronic periodontitis. We previously identified a Streptococcal ArcA derived Anti-P gingivalils Peptide (SAPP) that in vitro, is capable of repressing the expression of several virulence genes in the organism. This leads to a significant reduction in P gingivalis virulence potential, including its ability to colonize on the surface of Streptococcus gordonii, to invade human oral epithelial cells, and to produce gingipains. In this study, we showed that SAPP had minimal cytotoxicity to human oral keratinocytes and gingival fibroblasts. We observed that SAPP directly bound to the cell surface of P gingivalis, and that alterations in the sequence at the N-terminus of SAPP diminished its abilities to interact with P gingivalis cells and repressed the expression of virulence genes. Most strikingly, we demonstrated using an ex-vivo assay that besides its inhibitory activity against P gingivalis colonization, SAPP could also reduce the levels of several other oral Gram-negative bacteria strongly associated with periodontitis in multispecies biofilms. Our results provide a platform for the development of SAPP-targeted therapeutics against chronic periodontitis.
© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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13 MeSH Terms
Patients with familial adenomatous polyposis harbor colonic biofilms containing tumorigenic bacteria.
Dejea CM, Fathi P, Craig JM, Boleij A, Taddese R, Geis AL, Wu X, DeStefano Shields CE, Hechenbleikner EM, Huso DL, Anders RA, Giardiello FM, Wick EC, Wang H, Wu S, Pardoll DM, Housseau F, Sears CL
(2018) Science 359: 592-597
MeSH Terms: Adenomatous Polyposis Coli, Animals, Bacterial Toxins, Bacteroides fragilis, Biofilms, Carcinogenesis, Colon, Colonic Neoplasms, DNA Damage, Escherichia coli, Gastrointestinal Microbiome, Humans, Interleukin-17, Intestinal Mucosa, Metalloendopeptidases, Mice, Peptides, Polyketides, Precancerous Conditions
Show Abstract · Added March 20, 2018
Individuals with sporadic colorectal cancer (CRC) frequently harbor abnormalities in the composition of the gut microbiome; however, the microbiota associated with precancerous lesions in hereditary CRC remains largely unknown. We studied colonic mucosa of patients with familial adenomatous polyposis (FAP), who develop benign precursor lesions (polyps) early in life. We identified patchy bacterial biofilms composed predominately of and Genes for colibactin () and toxin (), encoding secreted oncotoxins, were highly enriched in FAP patients' colonic mucosa compared to healthy individuals. Tumor-prone mice cocolonized with (expressing colibactin), and enterotoxigenic showed increased interleukin-17 in the colon and DNA damage in colonic epithelium with faster tumor onset and greater mortality, compared to mice with either bacterial strain alone. These data suggest an unexpected link between early neoplasia of the colon and tumorigenic bacteria.
Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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19 MeSH Terms
Poly(glycidol) Coating on Ultrahigh Molecular Weight Polyethylene for Reduced Biofilm Growth.
Lockhart JN, Spoonmore TJ, McCurdy MW, Rogers BR, Guelcher SA, Harth E
(2018) ACS Appl Mater Interfaces 10: 4050-4056
MeSH Terms: Biofilms, Coated Materials, Biocompatible, Molecular Weight, Polyethylenes, Propylene Glycols, Staphylococcus aureus
Show Abstract · Added March 25, 2018
Semibranched poly(glycidol) (PG-OH) and poly(glycidol allylglycidyl ether) (PG-Allyl) coatings were formed on ultrahigh molecular weight polyethylene (UMWPE) in a unique two-step process which included radiation of UHMWPE followed by grafting of PG-OH or PG-Allyl to the surface via free radical cross-linking. Resulting surfaces were extensively characterized by FTIR-ATR, XPS, fluorescent microscopy, and contact goniometry. The performance was evaluated using the most prominent biofilm-forming bacteria Staphylococcus aureus for 24 and 48 h. The PG-Allyl coating demonstrated a 3 log reduction in biofilm growth compared to noncoated control, demonstrating a promising potential to inhibit adherence and colonization of biofilm-forming bacteria that often develop into persistent infections.
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6 MeSH Terms
Clinical investigation of biofilm in non-healing wounds by high resolution microscopy techniques.
Hurlow J, Blanz E, Gaddy JA
(2016) J Wound Care 25 Suppl 9: S11-22
MeSH Terms: Adolescent, Anti-Infective Agents, Local, Bandages, Biofilms, Debridement, Humans, Microscopy, Wound Healing, Wound Infection
Show Abstract · Added April 26, 2017
OBJECTIVE - The aim of this study was to analyse wound biofilm from a clinical perspective. Research has shown that biofilm is the preferred microbial phenotype in health and disease and is present in a majority of chronic wounds. Biofilm has been linked to chronic wound inflammation, impairment in granulation tissue and epithelial migration, yet there lacks the ability to confirm the clinical presence of biofilm. This study links the clinical setting with microscopic laboratory confirmation of the presence of biofilm in carefully selected wound debridement samples.
METHOD - Human wound debridement samples were collected from adult patients with chronic non-healing wounds who presented at the wound care centre. Sample choice was guided by an algorithm that was developed based on what is known about the characteristics of wound biofilm. The samples were then evaluated by light microscopy and scanning electron microscopy for the presence of biofilm. Details about subject history and treatment were recorded. Adherence to biofilm-based wound care (BBWC) strategies was inconsistent. Other standard antimicrobial dressings were used and no modern antiseptic wound dressings with the addition of proven antibiofilm agents were available for use.
RESULTS - Of the patients recruited, 75% of the macroscopic samples contained biofilm despite the prior use of modern antiseptic wound dressings and in some cases, systemic antibiotics. Wounds found to contain biofilm were not all acutely infected but biofilm was present when infection was noted. The clinical histories associated with positive samples were consistent with ideas presented in the algorithm used to guide sample selection.
CONCLUSION - Visual cues can be used by the clinician to guide suspicion of the presence of wound biofilm. This suspicion can be further enhanced with the use of a clinical algorithm. Standard antiseptic wound dressings used in this study demonstrated limited antibiofilm efficacy. This study also highlighted a need for the clinical team to focus on expiration of dressing action and consistent practice of BBWC strategies which includes the use of proven antibiofilm agents.
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9 MeSH Terms
Staphylococcus aureus Infection of Human Gestational Membranes Induces Bacterial Biofilm Formation and Host Production of Cytokines.
Doster RS, Kirk LA, Tetz LM, Rogers LM, Aronoff DM, Gaddy JA
(2017) J Infect Dis 215: 653-657
MeSH Terms: Biofilms, Chorioamnionitis, Cytokines, Drug Resistance, Multiple, Bacterial, Female, Humans, Infant, Newborn, Placenta, Pregnancy, Pregnancy Complications, Infectious, Premature Birth, Staphylococcal Infections, Staphylococcus aureus
Show Abstract · Added April 26, 2017
Staphylococcus aureus, a metabolically flexible gram-positive pathogen, causes infections in a variety of tissues. Recent evidence implicates S. aureus as an emerging cause of chorioamnionitis and premature rupture of membranes, which are associated with preterm birth and neonatal disease. We demonstrate here that S. aureus infects and forms biofilms on the choriodecidual surface of explanted human gestational membranes. Concomitantly, S. aureus elicits the production of proinflammatory cytokines, which could ultimately perturb maternal-fetal tolerance during pregnancy. Therefore, targeting the immunological response to S. aureus infection during pregnancy could attenuate disease among infected individuals, especially in the context of antibiotic resistance.
Published by Oxford University Press for the Infectious Diseases Society of America 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.
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13 MeSH Terms
Characterization of Key Helicobacter pylori Regulators Identifies a Role for ArsRS in Biofilm Formation.
Servetas SL, Carpenter BM, Haley KP, Gilbreath JJ, Gaddy JA, Merrell DS
(2016) J Bacteriol 198: 2536-48
MeSH Terms: Bacterial Proteins, Biofilms, Gene Expression Regulation, Bacterial, Helicobacter pylori, Trans-Activators
Show Abstract · Added April 26, 2017
UNLABELLED - Helicobacter pylori must be able to rapidly respond to fluctuating conditions within the stomach. Despite this need for constant adaptation, H. pylori encodes few regulatory proteins. Of the identified regulators, the ferric uptake regulator (Fur), the nickel response regulator (NikR), and the two-component acid response system (ArsRS) are each paramount to the success of this pathogen. While numerous studies have individually examined these regulatory proteins, little is known about their combined effect. Therefore, we constructed a series of isogenic mutant strains that contained all possible single, double, and triple regulatory mutations in Fur, NikR, and ArsS. A growth curve analysis revealed minor variation in growth kinetics across the strains; these were most pronounced in the triple mutant and in strains lacking ArsS. Visual analysis showed that strains lacking ArsS formed large aggregates and a biofilm-like matrix at the air-liquid interface. Biofilm quantification using crystal violet assays and visualization via scanning electron microscopy (SEM) showed that all strains lacking ArsS or containing a nonphosphorylatable form of ArsR (ArsR-D52N mutant) formed significantly more biofilm than the wild-type strain. Molecular characterization of biofilm formation showed that strains containing mutations in the ArsRS pathway displayed increased levels of cell aggregation and adherence, both of which are key to biofilm development. Furthermore, SEM analysis revealed prevalent coccoid cells and extracellular matrix formation in the ArsR-D52N, ΔnikR ΔarsS, and Δfur ΔnikR ΔarsS mutant strains, suggesting that these strains may have an exacerbated stress response that further contributes to biofilm formation. Thus, H. pylori ArsRS has a previously unrecognized role in biofilm formation.
IMPORTANCE - Despite a paucity of regulatory proteins, adaptation is key to the survival of H. pylori within the stomach. While prior studies have focused on individual regulatory proteins, such as Fur, NikR, and ArsRS, few studies have examined the combined effect of these factors. Analysis of isogenic mutant strains that contained all possible single, double, and triple regulatory mutations in Fur, NikR, and ArsS revealed a previously unrecognized role for the acid-responsive two-component system ArsRS in biofilm formation.
Copyright © 2016, American Society for Microbiology. All Rights Reserved.
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5 MeSH Terms
The innate immune protein calprotectin promotes Pseudomonas aeruginosa and Staphylococcus aureus interaction.
Wakeman CA, Moore JL, Noto MJ, Zhang Y, Singleton MD, Prentice BM, Gilston BA, Doster RS, Gaddy JA, Chazin WJ, Caprioli RM, Skaar EP
(2016) Nat Commun 7: 11951
MeSH Terms: Animals, Bacterial Proteins, Biofilms, Biosynthetic Pathways, Coinfection, Cystic Fibrosis, Humans, Immunity, Innate, Leukocyte L1 Antigen Complex, Manganese, Mice, Microbial Interactions, Proteomics, Pseudomonas Infections, Pseudomonas aeruginosa, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Staphylococcal Infections, Staphylococcus aureus, Zinc
Show Abstract · Added August 17, 2016
Microorganisms form biofilms containing differentiated cell populations. To determine factors driving differentiation, we herein visualize protein and metal distributions within Pseudomonas aeruginosa biofilms using imaging mass spectrometry. These in vitro experiments reveal correlations between differential protein distribution and metal abundance. Notably, zinc- and manganese-depleted portions of the biofilm repress the production of anti-staphylococcal molecules. Exposure to calprotectin (a host protein known to sequester metal ions at infectious foci) recapitulates responses occurring within metal-deplete portions of the biofilm and promotes interaction between P. aeruginosa and Staphylococcus aureus. Consistent with these results, the presence of calprotectin promotes co-colonization of the murine lung, and polymicrobial communities are found to co-exist in calprotectin-enriched airspaces of a cystic fibrosis lung explant. These findings, which demonstrate that metal fluctuations are a driving force of microbial community structure, have clinical implications because of the frequent occurrence of P. aeruginosa and S. aureus co-infections.
1 Communities
5 Members
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19 MeSH Terms
Association between genotypic diversity and biofilm production in group B Streptococcus.
Parker RE, Laut C, Gaddy JA, Zadoks RN, Davies HD, Manning SD
(2016) BMC Microbiol 16: 86
MeSH Terms: Animals, Bacterial Proteins, Biofilms, Cattle, Fimbriae, Bacterial, Genetic Variation, Genotype, Humans, Multilocus Sequence Typing, Phylogeny, Streptococcus agalactiae, Virulence Factors
Show Abstract · Added April 26, 2017
BACKGROUND - Group B Streptococcus (GBS) is a leading cause of sepsis and meningitis and an important factor in premature and stillbirths. Biofilm production has been suggested to be important for GBS pathogenesis alongside many other elements, including phylogenetic lineage and virulence factors, such as pili and capsule type. A complete understanding of the confluence of these components, however, is lacking. To identify associations between biofilm phenotype, pilus profile and lineage, 293 strains from asymptomatic carriers, invasive disease cases, and bovine mastitis cases, were assessed for biofilm production using an in vitro assay.
RESULTS - Multilocus sequence type (ST) profile, pilus island profile, and isolate source were associated with biofilm production. Strains from invasive disease cases and/or belonging to the ST-17 and ST-19 lineages were significantly more likely to form weak biofilms, whereas strains producing strong biofilms were recovered more frequently from individuals with asymptomatic colonization.
CONCLUSIONS - These data suggest that biofilm production is a lineage-specific trait in GBS and may promote colonization of strains representing lineages other than STs 17 and 19. The findings herein also demonstrate that biofilms must be considered in the treatment of pregnant women, particularly for women with heavy GBS colonization.
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12 MeSH Terms
Helicobacter pylori Resists the Antimicrobial Activity of Calprotectin via Lipid A Modification and Associated Biofilm Formation.
Gaddy JA, Radin JN, Cullen TW, Chazin WJ, Skaar EP, Trent MS, Algood HM
(2015) mBio 6: e01349-15
MeSH Terms: Acyltransferases, Anti-Bacterial Agents, Bacterial Proteins, Biofilms, Cell Membrane, Drug Resistance, Bacterial, Helicobacter pylori, Hydrophobic and Hydrophilic Interactions, Leukocyte L1 Antigen Complex, Lipid A, Lipopolysaccharides, Phenotype
Show Abstract · Added February 5, 2016
UNLABELLED - Helicobacter pylori is one of several pathogens that persist within the host despite a robust immune response. H. pylori elicits a proinflammatory response from host epithelia, resulting in the recruitment of immune cells which manifests as gastritis. Relatively little is known about how H. pylori survives antimicrobials, including calprotectin (CP), which is present during the inflammatory response. The data presented here suggest that one way H. pylori survives the nutrient sequestration by CP is through alteration of its outer membrane. CP-treated H. pylori demonstrates increased bacterial fitness in response to further coculture with CP. Moreover, CP-treated H. pylori cultures form biofilms and demonstrate decreased cell surface hydrophobicity. In response to CP, the H. pylori Lpx lipid A biosynthetic enzymes are not fully functional. The lipid A molecules observed in H. pylori cultures treated with CP indicate that the LpxF, LpxL, and LpxR enzyme functions are perturbed. Transcriptional analysis of lpxF, lpxL, and lpxR indicates that metal restriction by CP does not control this pathway through transcriptional regulation. Analyses of H. pylori lpx mutants reveal that loss of LpxF and LpxL results in increased fitness, similar to what is observed in the presence of CP; moreover, these mutants have significantly increased biofilm formation and reduced cell surface hydrophobicity. Taken together, these results demonstrate a novel mechanism of H. pylori resistance to the antimicrobial activity of CP via lipid A modification strategies and resulting biofilm formation.
IMPORTANCE - Helicobacter pylori evades recognition of the host's immune system by modifying the lipid A component of lipopolysaccharide. These results demonstrate for the first time that the lipid A modification pathway is influenced by the host's nutritional immune response. H. pylori's exposure to the host Mn- and Zn-binding protein calprotectin perturbs the function of 3 enzymes involved in the lipid A modification pathway. Moreover, CP treatment of H. pylori, or mutants with an altered lipid A, exhibit increased bacterial fitness and increased biofilm formation. This suggests that H. pylori modifies its cell surface structure to survive under the stress imposed by the host immune response. These results provide new insights into the molecular mechanisms that influence the biofilm lifestyle and how endotoxin modification, which renders H. pylori resistant to cationic antimicrobial peptides, can be inactivated in response to sequestration of nutrient metals.
Copyright © 2015 Gaddy et al.
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12 MeSH Terms