Dataset Information

Vertebrate TFPI-2 C-terminal peptides exert therapeutic applications against Gram-negative infections.

ABSTRACT: Tissue factor pathway inhibitor-2 (TFPI-2) is a serine protease inhibitor that exerts multiple physiological and patho-physiological activities involving the modulation of coagulation, angiogenesis, tumor invasion, and apoptosis. In previous studies we reported a novel role of human TFPI-2 in innate immunity by serving as a precursor for host defense peptides. Here we employed a number of TFPI-2 derived peptides from different vertebrate species and found that their antibacterial activity is evolutionary conserved although the amino acid sequence is not well conserved. We further studied the theraputic potential of one selected TFPI-2 derived peptide (mouse) in a murine sepsis model.Hydrophobicity and net charge of many peptides play a important role in their host defence to invading bacterial pathogens. In vertebrates, the C-terminal portion of TFPI-2 consists of a highly conserved cluster of positively charged amino acids which may point to an antimicrobial activity. Thus a number of selected C-terminal TFPI-2 derived peptides from different species were synthesized and it was found that all of them exert antimicrobial activity against E. coli and P. aeruginosa. The peptide-mediated killing of E. coli was enhanced in human plasma, suggesting an involvement of the classical pathway of the complement. Under in vitro conditions the peptides displayed anti-coagulant activity by modulating the intrinsic pathway of coagulation and in vivo treatment with the mouse derived VKG24 peptide protects mice from an otherwise lethal LPS shock model.Our results suggest that the evolutionary conserved C-terminal part of TFPI-2 is an interesting agent for the development of novel antimicrobial therapies.

SUBMITTER: Kasetty G

PROVIDER: S-EPMC4924314 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Vertebrate TFPI-2 C-terminal peptides exert therapeutic applications against Gram-negative infections.

Kasetty Gopinath G Smeds Emanuel E Holmberg Emelie E Wrange Louise L Adikesavan Selvi S Papareddy Praveen P

BMC microbiology 20160627 1

<h4>Background</h4>Tissue factor pathway inhibitor-2 (TFPI-2) is a serine protease inhibitor that exerts multiple physiological and patho-physiological activities involving the modulation of coagulation, angiogenesis, tumor invasion, and apoptosis. In previous studies we reported a novel role of human TFPI-2 in innate immunity by serving as a precursor for host defense peptides. Here we employed a number of TFPI-2 derived peptides from different vertebrate species and found that their antibacter ...[more]

PMID: 27349742

Similar Datasets

Project description:BackgroundClusters of bloodstream infections caused by Burkholderia cepacia and Stenotrophomonas maltophilia are uncommon, but have been previously identified in hemodialysis centers that reprocessed dialyzers for reuse on patients. We investigated an outbreak of bloodstream infections caused by B cepacia and S maltophilia among hemodialysis patients in clinics of a dialysis organization.Study designOutbreak investigation, including matched case-control study.Setting & participantsHemodialysis patients treated in multiple outpatient clinics owned by a dialysis organization.PredictorsMain predictors were dialyzer reuse, dialyzer model, and dialyzer reprocessing practice.OutcomesCase patients had a bloodstream infection caused by B cepacia or S maltophilia; controls were patients without infection dialyzed at the same clinic on the same day as a case; results of environmental cultures and organism typing.Results17 cases (9 B cepacia and 8 S maltophilia bloodstream infections) occurred in 5 clinics owned by the same dialysis organization. Case patients were more likely to have received hemodialysis with a dialyzer that had been used more than 6 times (matched OR, 7.03; 95% CI, 1.38-69.76) and to have been dialyzed with a specific reusable dialyzer (Model R) with sealed ends (OR, 22.87; 95% CI, 4.49-∞). No major lapses during dialyzer reprocessing were identified that could explain the outbreak. B cepacia was isolated from samples collected from a dialyzer header-cleaning machine from a clinic with cases and was indistinguishable from a patient isolate collected from the same clinic, by pulsed-field gel electrophoresis. Gram-negative bacteria were isolated from 2 reused Model R dialyzers that had undergone the facility's reprocessing procedure.LimitationsLimited statistical power and overmatching; few patient isolates and dialyzers available for testing.ConclusionsThis outbreak was likely caused by contamination during reprocessing of reused dialyzers. Results of this and previous investigations demonstrate that exposing patients to reused dialyzers increases the risk for bloodstream infections. To reduce infection risk, providers should consider implementing single dialyzer use whenever possible.

Project description:BACKGROUND:Rates of colonization and infection with carbapenem-resistant Gram-negative pathogens are on the rise, particularly in southeastern European countries, and this is increasingly true in Germany as well. The organisms in question include enterobacteriaceae such as Klebsiella pneumoniae and Escherichia coli and non-fermenting bacteria such as Pseudomonas aeruginosa and Acinetobacter baumannii. As the carbapenems have been the gold standard to date for the systemic treatment of serious infections with Gram-negative bacteria, carbapenem resistance presents new and difficult challenges in therapeutic decision-making, particularly because of the high frequency of coresistance. METHODS:This review is based on pertinent publications retrieved by a selective search in PubMed and on other applicable literature. RESULTS:Multiresistant Gram-negative (MRGN) pathogens are classified in Germany according to their resistance to four different classes of antibiotics; fluoroquinolones, piperacillin, third-generation cephalosporins, and carbapenems. Quadruple MRGN pathogens are resistant to all four groups, triple MRGN pathogens to three of them. There are a number of therapeutic alternatives to carbapenems that can be applied with the aid of sensitive microbiological and/or molecular genetic testing. The following antibiotics are often the only ones that can be used to treat quadruple MRGN pathogens: colistin, aminoglycosides, tigecycline, fosfomycin, ceftazidime/avibactam, and ceftolozan/tazobactam. Carbapenems, too, may still be an option in certain situations. There is also evidence that combinations of antibiotics against which the pathogen is resistant individually can some- times be a valid treatment option; these include combinations of colistin with one or two carbapenems. CONCLUSION:The treatment of severe infection with carbapenem-resistant pathogens should be individualized and carried out in an interdisciplinary framework, in consideration of antibiotic pharmacokinetics and pharmacodynamics in each case. The treat- ment options are based on evidence from in vitro studies, retrospective studies, and case series, which must be interpreted with caution. Randomized clinical trials are needed to test each of the various combined approaches.

Project description:The treatment of multidrug-resistant Gram-negative bacteria (MDR-GNB) infections in critically ill patients presents many challenges. Since an effective treatment should be administered as soon as possible, resistance to many antimicrobial classes almost invariably reduces the probability of adequate empirical coverage, with possible unfavorable consequences. In this light, readily available patient's medical history and updated information about the local microbiological epidemiology remain critical for defining the baseline risk of MDR-GNB infections and firmly guiding empirical treatment choices, with the aim of avoiding both undertreatment and overtreatment. Rapid diagnostics and efficient laboratory workflows are also of paramount importance both for anticipating diagnosis and for rapidly narrowing the antimicrobial spectrum, with de-escalation purposes and in line with antimicrobial stewardship principles. Carbapenem-resistant Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter baumannii are being reported with increasing frequencies worldwide, although with important variability across regions, hospitals and even single wards. In the past few years, new treatment options, such as ceftazidime/avibactam, meropenem/vaborbactam, ceftolozane/tazobactam, plazomicin, and eravacycline have become available, and others will become soon, which have provided some much-awaited resources for effectively counteracting severe infections due to these organisms. However, their optimal use should be guaranteed in the long term, for delaying as much as possible the emergence and diffusion of resistance to novel agents. Despite important progresses, pharmacokinetic/pharmacodynamic optimization of dosages and treatment duration in critically ill patients has still some areas of uncertainty requiring further study, that should take into account also resistance selection as a major endpoint. Treatment of severe MDR-GNB infections in critically ill patients in the near future will require an expert and complex clinical reasoning, of course taking into account the peculiar characteristics of the target population, but also the need for adequate empirical coverage and the more and more specific enzyme-level activity of novel antimicrobials with respect to the different resistance mechanisms of MDR-GNB.

Dataset Information

Vertebrate TFPI-2 C-terminal peptides exert therapeutic applications against Gram-negative infections.

Publications

Vertebrate TFPI-2 C-terminal peptides exert therapeutic applications against Gram-negative infections.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets