Commentary: Systems Biology Approach to Model the Life Cycle of Trypanosoma cruzi.

Front Cell Infect Microbiol. 2017;7:1

Authors: Carrea A, Diambra L

PMID: 28149830 [PubMed - in process]

Genes2GO: A web application for querying gene sets for specific GO terms.

Bioinformation. 2016;12(3):231-232

Authors: Chawla K, Kuiper M

Abstract
Gene ontology annotations have become an essential resource for biological interpretations of experimental findings. The process of gathering basic annotation information in tables that link gene sets with specific gene ontology terms can be cumbersome, in particular if it requires above average computer skills or bioinformatics expertise. We have therefore developed Genes2GO, an intuitive R-based web application. Genes2GO uses the biomaRt package of Bioconductor in order to retrieve custom sets of gene ontology annotations for any list of genes from organisms covered by the Ensembl database. Genes2GO produces a binary matrix file, indicating for each gene the presence or absence of specific annotations for a gene. It should be noted that other GO tools do not offer this user-friendly access to annotations.
AVAILABILITY: Genes2GO is freely available and listed under http://www.semantic-systems-biology.org/tools/externaltools/.

PMID: 28149059 [PubMed]

Mixing omics: combining genetics and metabolomics to study rheumatic diseases.

Nat Rev Rheumatol. 2017 Feb 02;:

Authors: Menni C, Zierer J, Valdes AM, Spector TD

Abstract
Metabolomics is an exciting field in systems biology that provides a direct readout of the biochemical activities taking place within an individual at a particular point in time. Metabolite levels are influenced by many factors, including disease status, environment, medications, diet and, importantly, genetics. Thanks to their dynamic nature, metabolites are useful for diagnosis and prognosis, as well as for predicting and monitoring the efficacy of treatments. At the same time, the strong links between an individual's metabolic and genetic profiles enable the investigation of pathways that underlie changes in metabolite levels. Thus, for the field of metabolomics to yield its full potential, researchers need to take into account the genetic factors underlying the production of metabolites, and the potential role of these metabolites in disease processes. In this Review, the methodological aspects related to metabolomic profiling and any potential links between metabolomics and the genetics of some of the most common rheumatic diseases are described. Links between metabolomics, genetics and emerging fields such as the gut microbiome and proteomics are also discussed.

PMID: 28148918 [PubMed - as supplied by publisher]

iPTMnet: Integrative Bioinformatics for Studying PTM Networks.

Methods Mol Biol. 2017;1558:333-353

Authors: Ross KE, Huang H, Ren J, Arighi CN, Li G, Tudor CO, Lv M, Lee JY, Chen SC, Vijay-Shanker K, Wu CH

Abstract
Protein post-translational modification (PTM) is an essential cellular regulatory mechanism, and disruptions in PTM have been implicated in disease. PTMs are an active area of study in many fields, leading to a wealth of PTM information in the scientific literature. There is a need for user-friendly bioinformatics resources that capture PTM information from the literature and support analyses of PTMs and their functional consequences. This chapter describes the use of iPTMnet ( http://proteininformationresource.org/iPTMnet/ ), a resource that integrates PTM information from text mining, curated databases, and ontologies and provides visualization tools for exploring PTM networks, PTM crosstalk, and PTM conservation across species. We present several PTM-related queries and demonstrate how they can be addressed using iPTMnet.

PMID: 28150246 [PubMed - in process]

Analysis of Protein Phosphorylation and Its Functional Impact on Protein-Protein Interactions via Text Mining of the Scientific Literature.

Methods Mol Biol. 2017;1558:213-232

Authors: Wang Q, Ross KE, Huang H, Ren J, Li G, Vijay-Shanker K, Wu CH, Arighi CN

Abstract
Post-translational modifications (PTMs) are one of the main contributors to the diversity of proteoforms in the proteomic landscape. In particular, protein phosphorylation represents an essential regulatory mechanism that plays a role in many biological processes. Protein kinases, the enzymes catalyzing this reaction, are key participants in metabolic and signaling pathways. Their activation or inactivation dictate downstream events: what substrates are modified and their subsequent impact (e.g., activation state, localization, protein-protein interactions (PPIs)). The biomedical literature continues to be the main source of evidence for experimental information about protein phosphorylation. Automatic methods to bring together phosphorylation events and phosphorylation-dependent PPIs can help to summarize the current knowledge and to expose hidden connections. In this chapter, we demonstrate two text mining tools, RLIMS-P and eFIP, for the retrieval and extraction of kinase-substrate-site data and phosphorylation-dependent PPIs from the literature. These tools offer several advantages over a literature search in PubMed as their results are specific for phosphorylation. RLIMS-P and eFIP results can be sorted, organized, and viewed in multiple ways to answer relevant biological questions, and the protein mentions are linked to UniProt identifiers.

PMID: 28150240 [PubMed - in process]

9 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"cystic fibrosis"

These pubmed results were generated on 2017/02/02

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Optimal knockout strategies in genome-scale metabolic networks using particle swarm optimization.

BMC Bioinformatics. 2017 Feb 01;18(1):78

Authors: Nair G, Jungreuthmayer C, Zanghellini J

Abstract
BACKGROUND: Knockout strategies, particularly the concept of constrained minimal cut sets (cMCSs), are an important part of the arsenal of tools used in manipulating metabolic networks. Given a specific design, cMCSs can be calculated even in genome-scale networks. We would however like to find not only the optimal intervention strategy for a given design but the best possible design too. Our solution (PSOMCS) is to use particle swarm optimization (PSO) along with the direct calculation of cMCSs from the stoichiometric matrix to obtain optimal designs satisfying multiple objectives.
RESULTS: To illustrate the working of PSOMCS, we apply it to a toy network. Next we show its superiority by comparing its performance against other comparable methods on a medium sized E. coli core metabolic network. PSOMCS not only finds solutions comparable to previously published results but also it is orders of magnitude faster. Finally, we use PSOMCS to predict knockouts satisfying multiple objectives in a genome-scale metabolic model of E. coli and compare it with OptKnock and RobustKnock.
CONCLUSIONS: PSOMCS finds competitive knockout strategies and designs compared to other current methods and is in some cases significantly faster. It can be used in identifying knockouts which will force optimal desired behaviors in large and genome scale metabolic networks. It will be even more useful as larger metabolic models of industrially relevant organisms become available.

PMID: 28143607 [PubMed - in process]

Dietary Nanosized Lactobacillus plantarum Enhances the Anticancer Effect of Kimchi on Azoxymethane and Dextran Sulfate Sodium-Induced Colon Cancer in C57BL/6J Mice.

J Environ Pathol Toxicol Oncol. 2016;35(2):147-59

Authors: Lee HA, Kim H, Lee KW, Park KY

Abstract
This study was undertaken to evaluate enhancement of the chemopreventive properties of kimchi by dietary nanosized Lactobacillus (Lab.)plantarum (nLp) in an azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced colitis-associated colorectal cancer C57BL/6J mouse model. nLp is a dead, shrunken, processed form of Lab. Plantarum isolated from kimchi that is 0.5-1.0 µm in size. The results obtained showed that animals fed kimchi with nLp (K-nLp) had longer colons and lower colon weights/length ratios and developed fewer tumors than mice fed kimchi alone (K). In addition, K-nLp administration reduced levels of proinflammatory cytokine serum levels and mediated the mRNA and protein expressions of inflammatory, apoptotic, and cell-cycle markers to suppress inflammation and induce tumor-cell apoptosis and cell-cycle arrest. Moreover, it elevated natural killer-cell cytotoxicity. The study suggests adding nLp to kimchi could improve the suppressive effect of kimchi on AOM/DSS-induced colorectal cancer. These findings indicate nLp has potential use as a functional chemopreventive ingredient in the food industry.

PMID: 27481492 [PubMed - indexed for MEDLINE]

7 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Rare Diseases"[Mesh] OR "orphan disease"

These pubmed results were generated on 2017/02/01

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Anthelminthic drug niclosamide sensitizes the responsiveness of cervical cancer cells to paclitaxel via oxidative stress-mediated mTOR inhibition.

Biochem Biophys Res Commun. 2017 Jan 27;:

Authors: Chen L, Wang L, Shen H, Lin H, Li D

Abstract
Drug repurposing represents an alternative therapeutic strategy to cancer treatment. The potent anti-cancer activities of a FDA-approved anthelminthic drug niclosamide have been demonstrated in various cancers. However, whether niclosamide is active against cervical cancer are unknown. In this study, we investigated the effects of niclosamide alone and its combination with paclitaxel in cervical cancer cells in vitro and in vivo. We found that niclosamide significantly inhibited proliferation and induced apoptosis of a panel of cervical cancer cell lines, regardless of their cellular origin and genetic pattern. Niclosamide also inhibited tumor growth in cervical cancer xenograft mouse model. Importantly, niclosamide significantly enhanced the responsiveness of cervical cancer cell to paclitaxel. We further found that niclosamide induced mitochondrial dysfunctions via inhibiting mitochondrial respiration, complex I activity and ATP generation, which led to oxidative stress. ROS scavenge agent N-acetyl-l-cysteine (NAC) completely reversed the effects of niclosamide in increasing cellular ROS, inhibiting proliferation and inducing apoptosis, suggesting that oxidative stress induction is the mechanism of action of niclosamide in cervical cancer cells. In addition, niclosamide significantly inhibited mammalian target of rapamycin (mTOR) signaling pathway in cervical cancer cells and its inhibitory effect on mTOR is modulated by oxidative stress. Our work suggests that niclosamide is a useful addition to the treatment armamentarium for cervical cancer and induction of oxidative stress may be a potential therapeutic strategy in cervical cancer.

PMID: 28137584 [PubMed - as supplied by publisher]

Toward cognitive pipelines of medical assistance algorithms.

Int J Comput Assist Radiol Surg. 2016 Sep;11(9):1743-53

Authors: Philipp P, Maleshkova M, Katic D, Weber C, Götz M, Rettinger A, Speidel S, Kämpgen B, Nolden M, Wekerle AL, Dillmann R, Kenngott H, Müller B, Studer R

Abstract
PURPOSE: Assistance algorithms for medical tasks have great potential to support physicians with their daily work. However, medicine is also one of the most demanding domains for computer-based support systems, since medical assistance tasks are complex and the practical experience of the physician is crucial. Recent developments in the area of cognitive computing appear to be well suited to tackle medicine as an application domain.
METHODS: We propose a system based on the idea of cognitive computing and consisting of auto-configurable medical assistance algorithms and their self-adapting combination. The system enables automatic execution of new algorithms, given they are made available as Medical Cognitive Apps and are registered in a central semantic repository. Learning components can be added to the system to optimize the results in the cases when numerous Medical Cognitive Apps are available for the same task. Our prototypical implementation is applied to the areas of surgical phase recognition based on sensor data and image progressing for tumor progression mappings.
RESULTS: Our results suggest that such assistance algorithms can be automatically configured in execution pipelines, candidate results can be automatically scored and combined, and the system can learn from experience. Furthermore, our evaluation shows that the Medical Cognitive Apps are providing the correct results as they did for local execution and run in a reasonable amount of time.
CONCLUSION: The proposed solution is applicable to a variety of medical use cases and effectively supports the automated and self-adaptive configuration of cognitive pipelines based on medical interpretation algorithms.

PMID: 26646415 [PubMed - indexed for MEDLINE]

The importance of drug transporter characterization to precision medicine.

Expert Opin Drug Metab Toxicol. 2017 Jan 31;:

Authors: Fisel P, Nies AT, Schaeffeler E, Schwab M

PMID: 28140687 [PubMed - as supplied by publisher]

Pharmacogenomics of 17-alpha hydroxyprogesterone caproate for recurrent preterm birth: a case-control study.

BJOG. 2017 Jan 31;:

Authors: Manuck TA, Watkins WS, Esplin MS, Biggio J, Bukowski R, Parry S, Zhan H, Huang H, Andrews W, Saade G, Sadovsky Y, Reddy UM, Ilekis J, Yandell M, Varner MW, Jorde LB, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Genomics and Proteomics Network for Preterm Birth Research (GPN-PBR)

Abstract
OBJECTIVE: To compare maternal genotypes between women with and without significant prolongation of pregnancy in the setting of 17-alpha hydroxyprogesterone caproate (17-P) administration for the prevention of recurrent preterm birth (PTB).
DESIGN: Case-control.
SETTING: Three tertiary-care centres across the USA.
POPULATION: Women (n = 99) with ≥ 1 prior singleton spontaneous PTB, receiving 17-P.
METHODS: Women were classified as having successful prolongation of pregnancy during the 17-P treated pregnancy, in two ways: (1) Definition A: success/non-success based on difference in gestational age at delivery between 17-P-treated and untreated pregnancies (success: delivered ≥ 3 weeks later with 17-P) and (2) Definition B: success/non-success based on reaching term (success: delivered at term with 17-P).
MAIN OUTCOME MEASURES: To assess genetic variation, all women underwent whole exome sequencing. Between-group sequence variation was analysed with the Variant Annotation, Analysis, and Search Tool (VAAST). Genes scored by VAAST with P < 0.05 were then analysed with two online tools: (1) Protein ANalysis THrough Evolutionary Relationships (PANTHER) and (2) Database for Annotation, Visualization, and Integrated Discovery (DAVID).
RESULTS: Using Definition A, there were 70 women with successful prolongation and 29 without; 1375 genes scored by VAAST had P < 0.05. Using Definition B, 47 women had successful prolongation and 52 did not; 1039 genes scored by VAAST had P < 0.05. PANTHER revealed key differences in gene ontology pathways. Many genes from definition A were classified as prematurity genes (P = 0.026), and those from definition B as pharmacogenetic genes (P = 0.0018); (P, non-significant after Bonferroni correction).
CONCLUSION: A novel analytic approach revealed several genetic differences among women delivering early vs later with 17-P.
TWEETABLE ABSTRACT: Several key genetic differences are present in women with recurrent preterm birth despite 17-P treatment.

PMID: 28139890 [PubMed - as supplied by publisher]

Novel genetic variants in carboxylesterase 1 predict severe early-onset capecitabine-related toxicity.

Clin Pharmacol Ther. 2017 Jan 31;:

Authors: Hamzic S, Kummer D, Milesi S, Mueller D, Joerger M, Aebi S, Amstutz U, Largiadèr CR

Abstract
An important concern with the anticancer drug capecitabine (Cp), an oral prodrug of 5-fluorouracil, are dose-limiting adverse effects, in particular hand-foot syndrome (HFS) and diarrhea. Here, we evaluated the association of genetic variability in all enzymes of the Cp-activation pathway to 5-fluorouracil with Cp-related early-onset toxicity in 144 patients receiving Cp. We identified a haplotype encompassing five variants in the carboxylesterase 1 (CES1) gene region including an expression quantitative trait locus (Haplotype A3: ORadditive =2.2, 95%CI 1.2-4.0, Padjusted =0.012; ORrecessive =10.3, 95%CI 2.1-49.4, Padjusted = 0.0038) associated with early-onset Cp-toxicity. Furthermore, the association of two linked cytidine deaminase (CDA) promoter variants (c.1-451C>T: ORdominant =4.3, 95%CI 1.3-14.2, Padjusted =0.017; and c.1-92A>G: ORdominant =4.4, 95%CI 1.3-14.5, Padjusted =0.015) with Cp-related diarrhea was replicated. This first study identifying an association of genetic variation in CES1 with Cp-related toxicity provides further evidence for the existence of a functional noncoding CES1-variant with a possible regulatory impact. This article is protected by copyright. All rights reserved.

PMID: 28139840 [PubMed - as supplied by publisher]

Genetically determined high activity of IL-12 and IL-18 in ulcerative colitis and TLR5 in Crohns disease were associated with non-response to anti-TNF therapy.

Pharmacogenomics J. 2017 Jan 31;:

Authors: Bank S, Andersen PS, Burisch J, Pedersen N, Roug S, Galsgaard J, Turino SY, Brodersen JB, Rashid S, Rasmussen BK, Avlund S, Olesen TB, Hoffmann HJ, Nexø BA, Sode J, Vogel U, Andersen V

Abstract
Anti-tumour necrosis factor-α (TNF-α) is used for treatment of severe cases of inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC). However, one-third of the patients do not respond to the treatment. A recent study indicated that genetically determined high activity of pro-inflammatory cytokines, including interleukin-1β (IL-1β), IL-6 and interferon gamma (IFN-γ), are associated with non-response to anti-TNF therapy. Using a candidate gene approach, 21 functional single-nucleotide polymorphisms (SNPs) in 14 genes in the Toll-like receptors, the inflammasome and the IFNG pathways were assessed in 482 and 256 prior anti-TNF naïve Danish patients with CD and UC, respectively. The results were analysed using logistic regression (adjusted for age and gender). Eight functional SNPs were associated with anti-TNF response either among patients with CD (TLR5 (rs5744174) and IFNGR2 (rs8126756)), UC (IL12B (rs3212217), IL18 (rs1946518), IFNGR1 (rs2234711), TBX21 (rs17250932) and JAK2 (rs12343867)) or in the combined cohort of patient with CD and UC (IBD) (NLRP3 (rs10754558), IL12B (rs3212217) and IFNGR1 (rs2234711)) (P<0.05). Only the association with heterozygous genotype of IL12B (rs3212217) (OR: 0.24, 95% CI: 0.11-0.53, P=0.008) among patients with UC withstood Bonferroni correction for multiple testing. In conclusion, Our results suggest that SNPs associated with genetically determined high activity of TLR5 among patients with CD and genetically determined high IL-12 and IL-18 levels among patients with UC were associated with non-response. Further studies will evaluate whether these genes may help stratifying patients according to the expected response to anti-TNF treatment.The Pharmacogenomics Journal advance online publication, 31 January 2017; doi:10.1038/tpj.2016.84.

PMID: 28139755 [PubMed - as supplied by publisher]

Analysis of Pseudomonas aeruginosa PAO1 Biofilm Protein Profile After Exposure to n-Butanolic Cyclamen coum Extract Alone and in Combination with Ciprofloxacin.

Appl Biochem Biotechnol. 2017 Jan 30;:

Authors: Shafiei M, Abdi-Ali A, Shahcheraghi F, Vali H, Shahbani Zahiri H, Akbari Noghabi K

Abstract
Pseudomonas aeruginosa biofilm-related infections are the major cause of premature death in cystic fibrosis patients. Strategies to induce biofilm dispersal are of interest, because of their potential in preventing biofilm-related infections. Our previous work demonstrated that n-butanolic Cyclamen coum extract with ciprofloxacin could eliminate 1- and 3-day-old P. aeruginosa PAO1 biofilms. To gain new insights into the role of C. coum extract and its synergistic effect with ciprofloxacin in eliminating P. aeruginosa PAO1 biofilms, two-dimensional gel electrophoresis (2-DE) in combination with mass spectrometry-based protein identification were used. Changes in the bacterial protein expression were analyzed when 3-day-old biofilm cells were exposed to the C. coum extract alone and in combination with ciprofloxacin. Proteins involved in alginate biosynthesis, quorum sensing, adaptation/protection, carbohydrate and amino acid metabolism showed a weaker expression in the C. coum extract-ciprofloxacin-treated biofilm cells compared to those in the untreated cells. Interestingly, the proteome of C. coum extract-ciprofloxacin-treated biofilm revealed more resemblance to the planktonic phenotype than to the biofilm phenotype. It appears that saponin extract in combination with ciprofloxacin causes biofilm disruption due to several mechanisms such as motility induction, cell envelope integrity perturbation, stress protein expression reduction, and more importantly, signal transduction perturbation. In conclusion, exposure to a combination of biofilm dispersal such as saponin extract and antimicrobial agents may offer a novel strategy to control preestablished, persistent P. aeruginosa biofilms and biofilm-related infections.

PMID: 28138928 [PubMed - as supplied by publisher]

Achromobacter xylosoxidans infection in cystic fibrosis siblings with different outcomes: Case reports.

Respir Med Case Rep. 2017;20:98-103

Authors: Firmida MC, Marques EA, Leão RS, Pereira RH, Rodrigues ER, Albano RM, Folescu TW, Bernardo V, Daltro P, Capone D, Lopes AJ

Abstract
INTRODUCTION: The clinical relevance of Achromobacter xylosoxidans infection in cystic fibrosis (CF) remains controversial. This emerging agent in CF has been associated with increased lung inflammation, more frequent exacerbations and more severe lung disease. We describe a pair of CF siblings chronically colonized by the same multilocus genotype of A. xylosoxidans with different clinical courses, and assess whether this species may have developed any virulence traits and antimicrobial resistance that could have contributed to their singular outcomes.
CASE PRESENTATION: Two siblings were positive for the F508del and Y1092X mutations, and were chronically colonized by Pseudomonas aeruginosa and Staphylococcus aureus. The female patient had a more severe CF phenotype and faster clinical deterioration than her brother. Her pulmonary function and computed tomography scan lesions were worse than those of her brother, and both parameters progressively declined. She died at 14 years of age, when he was 18. All isolates of A. xylosoxidans were biofilm producers. Achromobacter xylosoxidans showed less swarming motility in the female patient.
CONCLUSIONS: Biofilm production and diminution of motility allow persistence. Only swarming motility differed between the isolates recovered from the two siblings, but this finding is not sufficient to explain the different clinical outcomes despite their similar genotypes. Modifier genes, unknown environmental factors and female gender can partially explain differences between these siblings. We were unable to correlate any microbiological findings with their clinical courses, and more translational studies are necessary to decrease the gap of knowledge between laboratory and clinical data to promote better clinical interventions.

PMID: 28138423 [PubMed - in process]

Inhibition of Pseudomonas aeruginosa by Peptide-conjugated Phosphorodiamidate Morpholino Oligomers.

Antimicrob Agents Chemother. 2017 Jan 30;:

Authors: Howard JJ, Sturge CR, Moustafa DA, Daly SM, Marshall-Batty KR, Felder CF, Zamora D, Yabe-Gill M, Labandeira-Rey M, Bailey SM, Wong M, Goldberg JB, Geller BL, Greenberg DE

Abstract
Pseudomonas aeruginosa is a highly virulent, multidrug-resistant pathogen that causes significant morbidity and mortality in hospitalized patients and is particularly devastating in those with cystic fibrosis (CF). Increasing antibiotic resistance coupled with decreasing numbers of antibiotics in the developmental pipeline demands novel antibacterial approaches. Here we tested peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs), which inhibit translation of complementary mRNA from specific, essential genes in P. aeruginosa PPMOs targeted to acpP, lpxC, and rpsJ, inhibited P. aeruginosa growth in many clinical strains and activity of PPMOs could be enhanced 2- to 8-fold by the addition of polymyxin B nonapeptide (PMBN) at sub-inhibitory concentrations. The PPMO targeting acpP was also effective at preventing P. aeruginosa PAO1 biofilm formation and at reducing existing biofilms. Importantly, treatment with various combinations of a PPMO and a traditional antibiotic demonstrated synergistic growth inhibition, the most effective of which was the PPMO targeting rpsJ with tobramycin. Furthermore, treatment of P. aeruginosa PA103 infected mice with PPMOs targeting acpP, lpxC, or rpsJ significantly reduced bacterial burden in the lungs at 24 hours by almost three logs. Altogether, this study demonstrates that PPMOs targeting the essential genes acpP, lpxC, or rpsJ in P. aeruginosa are highly effective at inhibiting growth in vitro and in vivo. These data suggest that PPMOs alone or in combination with antibiotics represent a novel approach to address the problems associated with rapidly increasing antibiotic resistance in P. aeruginosa.

PMID: 28137807 [PubMed - as supplied by publisher]

Importance of the exopolysaccharide matrix in antimicrobial tolerance of Pseudomonas aeruginosa aggregates.

Antimicrob Agents Chemother. 2017 Jan 30;:

Authors: Goltermann L, Tolker-Nielsen T

Abstract
Pseudomonas aeruginosa is an opportunistic pathogen that can infect the lungs of cystic fibrosis (CF) patients, and persist in the form of antibiotic tolerant aggregates in the mucus. It has recently been suggested that such aggregates are formed due to restricted bacterial motility independent of the production of extracellular matrix components, and that they do not rely on an extracellular matrix for antimicrobial tolerance. However, we show here that biofilm matrix over-expression, as displayed by various clinical isolates, significantly protects P. aeruginosa aggregates against antimicrobial treatment. Alginate-overproducing mucA mutant bacteria growing in aggregates showed highly increased antibiotic tolerance compared to wild type bacteria in aggregates. Deletion of algD in the mucA strain abrogated alginate production and reversed the antibiotic tolerance displayed by the aggregates to a level similar to that observed for aggregates formed by the wild type. The mutant strains P. aeruginosa ΔwspF and ΔyfiR both over-produce Pel and Psl exopolysaccharide, and when these bacteria grew in aggregates they showed highly increased antibiotic tolerance compared to wild type bacteria growing in aggregates. However, ΔwspF and ΔyfiR mutant strains, deficient in Pel/Psl production due to additional ΔpelAΔpslBCD deletions, formed aggregates that displayed antibiotic tolerance levels close to that of wild type aggregates. These results suggest that biofilm matrix components such as alginate, Pel and Psl do play a role in the tolerance towards antimicrobials when bacteria grow as aggregates.

PMID: 28137803 [PubMed - as supplied by publisher]

The mechanism of killing by the proline-rich peptide Bac7(1-35) against clinical strains of Pseudomonas aeruginosa differs from that showed against other Gram-negative bacteria.

Antimicrob Agents Chemother. 2017 Jan 30;:

Authors: Runti G, Benincasa M, Giuffrida G, Devescovi G, Venturi V, Gennaro R, Scocchi M

Abstract
P. aeruginosa infections represent a serious threat to worldwide health. Proline-rich antimicrobial peptides (PR-AMPs), a particular group of peptide antibiotics, have demonstrated in vitro activity against P. aeruginosa strains. Here we show that the mammalian PR-AMP Bac7 (1-35) is active against some multi-drug-resistant cystic fibrosis isolates of P. aeruginosa By confocal microscopy and cytometric analyses we investigated the mechanism of killing against P. aeruginosa PAO1 and three selected isolates and we observed that the peptide inactivated the target cells by disrupting their cellular membranes. This effect is deeply different from that previously described for PR-AMPs in E. coli and S. typhimurium, where these peptides act intracellularly after having been internalized by means of the transporter SbmA without membranolytic effects. The heterologous expression of SbmA in PAO1 cells enhanced the internalization of Bac7 (1-35) into the cytoplasm making the bacteria more susceptible to the peptide, but at the same time more resistant to the membrane lysis similarly to what occurs in E. coli Results evidenced a new mechanism of action for PR-AMPs and indicate that Bac7 has multiple and variable modes of action that depends on the characteristics of the different target species and the possibility to be internalized by bacterial transporters. This feature broadens the spectrum of activity of the peptide and makes the development of peptide-resistant bacteria a more difficult process.

PMID: 28137800 [PubMed - as supplied by publisher]