DOCSLIB.ORG

Phylogenetic and Functional Analyses of Stress-Responsive Bacterial Transmembrane Signal Transducing Systems

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Phylogenetic and Functional Analyses of Stress-Responsive Bacterial Transmembrane Signal Transducing Systems Phylogenetic and functional analyses of stress-responsive bacterial transmembrane signal transducing systems Dissertation zur Erlangung des Doktorgrades der Fakultät für Biologie der Ludwig-Maximilians-Universität München vorgelegt von Anna Staro ń aus Warschau München 2012 Erstgutachter: Prof. Dr. Thorsten Mascher Zweitgutachter: Prof. Dr. Heinrich Jung Tag der mündlichen Prüfung: 24.10.2012 Eidesstattliche Versicherung und Erklärung Hiermit versichere ich an Eides statt, dass die vorliegende Dissertation von mir selbständig und ohne unerlaubte Hilfe angefertigt wurde. Zudem wurden keine anderen als die angegebenen Quellen verwendet. Außerdem versichere ich, dass die Dissertation keiner anderen Prüfungskommission vorgelegt wurde und ich mich nicht anderweitig einer Doktorprüfung ohne Erfolg unterzogen habe. München, 13.06.2012 _____________ Anna Staro ń I Content Abbreviations .......................................................................................................................... IX List of publications .................................................................................................................. X Author contrtibutions .......................................................................................................... XII Summary .............................................................................................................................. XIV Zusammenfassung ................................................................................................................ XV Chapter 1 Introduction .............................................................................................................................. 1 1.1. Principles of bacterial signal transductions ......................................................................... 2 1.1.1. One-component signal transduction systems ............................................................ 2 1.1.2. Two-component signal transduction systems ............................................................ 4 1.1.3. ECF σ Factors ............................................................................................................ 5 1.2. Bce-like detoxification modules .......................................................................................... 6 1.2.1. Experimentally characterized Bce-like systems ........................................................ 8 1.2.2. Common themes in Bce-like systems...................................................................... 12 1.2.2.1. Stimuli sensed by Bce-like systems ............................................................ 12 1.2.2.2. Role of the BceAB-like ABC transporters in sensing and detoxification .. 13 1.2.2.3. Signalling versus resistance in Bce-like detoxification modules ................ 14 1.2.2.4. Mechanism of stimulus perception in Bce-like systems: different possibilities .............................................................................................................. 15 1.2.2.5. Additional BceR-target genes ..................................................................... 16 1.2.2.6. BceR-like binding sites ............................................................................... 17 1.2.2.7. Extended Bce regulons and functions ......................................................... 17 1.3. Aims of this work .............................................................................................................. 19 Chapter 2 The third pillar of bacterial signal transduction: classification of the extracytoplasmic function (ECF) σ factor protein family ................................................................................. 20 2.1. Introduction ....................................................................................................................... 21 2.2. Results and discussion ....................................................................................................... 24 2.2.1. Identification and grouping of ECF σ factors .......................................................... 24 2.2.2. Major and minor groups of ECF σ factors .............................................................. 25 II 2.2.3. Effect of genome sequence availability bias on the ECF classification .................. 32 2.2.4. Distribution and phylum-specific patterns of ECF σ factors ................................... 33 2.2.5. Robustness, sensitivity and limitations of the ECF group-specific HMMs ............ 35 2.2.6. Identification and analysis of anti-σ factors specific for ECF groups ..................... 37 2.2.7. Genomic context conservation within ECF groups ................................................. 42 2.2.8. Detailed description of the major ECF groups ........................................................ 43 2.2.8.1. ECF01-ECF04 – RpoE-like ECF σ factors ................................................. 43 2.2.8.2. ECF05-ECF10 – FecI-like ECF σ factors ................................................... 44 2.2.8.3. ECF11-ECF15 – cytoplasmic-sensing ECF σ factors ................................. 45 2.2.8.3.1. ECF11 .......................................................................................... 45 2.2.8.3.2. ECF12 .......................................................................................... 46 2.2.8.3.3. ECF13 .......................................................................................... 46 2.2.8.3.4. ECF14 .......................................................................................... 46 2.2.8.3.5. ECF15 – EcfG-like ....................................................................... 46 2.2.8.4. Features of the remaining major ECF groups ............................................. 48 2.2.8.4.1. ECF16 – SigF-like ........................................................................ 49 2.2.8.4.2. ECF17 – SigU-like ....................................................................... 49 2.2.8.4.3. ECF18 – RpoT-like ...................................................................... 49 2.2.8.4.4. ECF19 – SigK-like ....................................................................... 49 2.2.8.4.5. ECF20 .......................................................................................... 49 2.2.8.4.6. ECF21-25 ..................................................................................... 50 2.2.8.4.7. ECF26 .......................................................................................... 50 2.2.8.4.8. ECF27 .......................................................................................... 51 2.2.8.4.9. ECF28 .......................................................................................... 51 2.2.8.4.10. ECF29 ........................................................................................ 51 2.2.8.4.11. ECF30 ........................................................................................ 51 2.2.8.4.12. ECF31 ........................................................................................ 51 2.2.8.4.13. ECF32 – HrpL-like .................................................................... 51 2.2.8.4.14. ECF33/34 ................................................................................... 52 2.2.8.4.15. ECF35 ........................................................................................ 52 2.2.8.4.16. ECF36-40 ................................................................................... 52 2.2.8.4.17. ECF41 ........................................................................................ 53 2.2.8.4.18. ECF42 ........................................................................................ 53 2.2.8.4.19. ECF43 – ECF-like proteins ........................................................ 53 III 2.2.9. Identification of group-specific ECF target promoter motifs .................................. 54 2.2.10. Nomenclature of ECF σ factors ............................................................................. 55 2.2.11. Summary and outlook: resources to study ECF σ factors, the third pillar of bacterial signal transduction .............................................................................................. 56 2.3. Experimental procedure ..................................................................................................... 57 2.3.1. Sequence retrieval ................................................................................................... 57 2.3.2. Classification of ECF σ factors by multiple sequence alignments and genomic context clustering .............................................................................................................. 57 2.3.3. Identification and classification of anti-σ factors .................................................... 58 2.3.4. Construction and evaluation of HMM models ........................................................ 58 2.3.5. Implementation of ECF finder ................................................................................. 58 2.3.6. Identification of group-specific target promoters .................................................... 59 2.4. Acknowledgements ........................................................................................................... 59 Chapter 3 General stress response in α-proteobacteria: PhyR and beyond ....................................... 60 3.1. Introduction ......................................................................................................................
Load more

Recommended publications
  • A Novel Secretion and Online-Cleavage Strategy for Production of Cecropin a in Escherichia Coli
    www.nature.com/scientificreports OPEN A novel secretion and online- cleavage strategy for production of cecropin A in Escherichia coli Received: 14 March 2017 Meng Wang 1, Minhua Huang1, Junjie Zhang1, Yi Ma1, Shan Li1 & Jufang Wang1,2 Accepted: 23 June 2017 Antimicrobial peptides, promising antibiotic candidates, are attracting increasing research attention. Published: xx xx xxxx Current methods for production of antimicrobial peptides are chemical synthesis, intracellular fusion expression, or direct separation and purifcation from natural sources. However, all these methods are costly, operation-complicated and low efciency. Here, we report a new strategy for extracellular secretion and online-cleavage of antimicrobial peptides on the surface of Escherichia coli, which is cost-efective, simple and does not require complex procedures like cell disruption and protein purifcation. Analysis by transmission electron microscopy and semi-denaturing detergent agarose gel electrophoresis indicated that fusion proteins contain cecropin A peptides can successfully be secreted and form extracellular amyloid aggregates at the surface of Escherichia coli on the basis of E. coli curli secretion system and amyloid characteristics of sup35NM. These amyloid aggregates can be easily collected by simple centrifugation and high-purity cecropin A peptide with the same antimicrobial activity as commercial peptide by chemical synthesis was released by efcient self-cleavage of Mxe GyrA intein. Here, we established a novel expression strategy for the production of antimicrobial peptides, which dramatically reduces the cost and simplifes purifcation procedures and gives new insights into producing antimicrobial and other commercially-viable peptides. Because of their potent, fast, long-lasting activity against a broad range of microorganisms and lack of bacterial resistance, antimicrobial peptides (AMPs) have received increasing attention1.
    [Show full text]
  • Novel Therapeutic Interventions Towards Improved Management of Septic Arthritis Jian Wang1* and Liucai Wang2
    Wang and Wang BMC Musculoskeletal Disorders (2021) 22:530 https://doi.org/10.1186/s12891-021-04383-6 REVIEW Open Access Novel therapeutic interventions towards improved management of septic arthritis Jian Wang1* and Liucai Wang2 Abstract Septic arthritis (SA) represents a medical emergency that needs immediate diagnosis and urgent treatment. Despite aggressive treatment and rapid diagnosis of the causative agent, the mortality and lifelong disability, associated with septic arthritis remain high as close to 11%. Moreover, with the rise in drug resistance, the rates of failure of conventional antibiotic therapy have also increased. Among the etiological agents frequently isolated from cases of septic arthritis, Staphylococcus aureus emerges as a dominating pathogen, and to worsen, the rise in methicillin- resistant S. aureus (MRSA) isolates in bone and joint infections is worrisome. MRSA associated cases of septic arthritis exhibit higher mortality, longer hospital stay, and higher treatment failure with poorer clinical outcomes as compared to cases caused by the sensitive strain i.e methicillin-sensitive S. aureus (MSSA). In addition to this, equal or even greater damage is imposed by the exacerbated immune response mounted by the patient’s body in a futile attempt to eradicate the bacteria. The antibiotic therapy may not be sufficient enough to control the progression of damage to the joint involved thus, adding to higher mortality and disability rates despite the prompt and timely start of treatment. This situation implies that efforts and focus towards studying/ understanding new strategies for improved management of sepsis arthritis is prudent and worth exploring. The review article aims to give a complete insight into the new therapeutic approaches studied by workers lately in this field.
    [Show full text]
  • Design, Development, and Characterization of Novel Antimicrobial Peptides for Pharmaceutical Applications Yazan H
    University of Arkansas, Fayetteville ScholarWorks@UARK Theses and Dissertations 8-2013 Design, Development, and Characterization of Novel Antimicrobial Peptides for Pharmaceutical Applications Yazan H. Akkam University of Arkansas, Fayetteville Follow this and additional works at: http://scholarworks.uark.edu/etd Part of the Biochemistry Commons, Medicinal and Pharmaceutical Chemistry Commons, and the Molecular Biology Commons Recommended Citation Akkam, Yazan H., "Design, Development, and Characterization of Novel Antimicrobial Peptides for Pharmaceutical Applications" (2013). Theses and Dissertations. 908. http://scholarworks.uark.edu/etd/908 This Dissertation is brought to you for free and open access by ScholarWorks@UARK. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of ScholarWorks@UARK. For more information, please contact [email protected], [email protected]. Design, Development, and Characterization of Novel Antimicrobial Peptides for Pharmaceutical Applications Design, Development, and Characterization of Novel Antimicrobial Peptides for Pharmaceutical Applications A Dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Cell and Molecular Biology by Yazan H. Akkam Jordan University of Science and Technology Bachelor of Science in Pharmacy, 2001 Al-Balqa Applied University Master of Science in Biochemistry and Chemistry of Pharmaceuticals, 2005 August 2013 University of Arkansas This dissertation is approved for recommendation to the Graduate Council. Dr. David S. McNabb Dissertation Director Professor Roger E. Koeppe II Professor Gisela F. Erf Committee Member Committee Member Professor Ralph L. Henry Dr. Suresh K. Thallapuranam Committee Member Committee Member ABSTRACT Candida species are the fourth leading cause of nosocomial infection. The increased incidence of drug-resistant Candida species has emphasized the need for new antifungal drugs.
    [Show full text]
  • Resistance to Host Antimicrobial Peptides Is Necessaryfor
    Proc. Nati. Acad. Sci. USA Vol. 89, pp. 11939-11943, December 1992 Genetics Resistance to host antimicrobial peptides is necessary for Salmonella virulence (transposon mutagenesis/defensin/magainin/cecropin/pathogenesis) EDUARDO A. GROISMAN*t, CARLOS PARRA-LOPEZ*, MARGARITA SALCEDO*, CRAIG J. Lippst, AND FRED HEFFRON*§ *Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110; tDepartment of Molecular Biology, Research Institute of Scripps Clinic, La Jolla, CA 92037; and §Department of Microbiology and Immunology, Oregon Health Sciences University, Portland, OR 97201 Communicated by David M. Kipnis, September 14, 1992 ABSTRACT The production of antibacterial peptides is a distinct strategies to evade killing by the phagocyte oxygen- host defense strategy used by various species, including mam- dependent and -independent mechanisms (3). mals, amphibians, and insects. Successful pathogens, such as To cause disease, Salmonella must withstand the battery of the facultative intracellular bacterium Salmonella typhimu- short peptides with antibiotic activity present in phagocytic num, have evolved resistance mechanisms to this ubiquitous cells and other tissues. One such group of peptides is the type of host defense. To identify the genes required for resis- defensins, which are abundant in the azurophilic granules of tance to host peptides, we isolated a library of 20,000 MudJ neutrophils and macrophages from rabbits, rats, guinea pigs, transposon insertion mutants of a virulent peptide-resistant S. and humans and the crypt cells of mouse intestine (4). The typhimurium strain and screened it for hypersensitivity to the importance of these peptides for host defense is underscored antimicrobial peptide protamine. Eighteen mutants had by the fact that patients with specialized granule deficiency- heightened susceptibility to protamine and 12 of them were who lack defensins-have recurrent infections (5).
    [Show full text]
  • Analysis of the Solution Structure of the Human Antibiotic Peptide Dermcidin and Its Interaction with Phospholipid Vesicles
    BMB reports Analysis of the solution structure of the human antibiotic peptide dermcidin and its interaction with phospholipid vesicles Hyun Ho Jung1, Sung-Tae Yang2, Ji-Yeong Sim1, Seungkyu Lee1, Ju Yeon Lee1, Ha Hyung Kim3, Song Yub Shin4 & Jae Il Kim1,* 1Department of Life Science, Gwangju Institute of Science and Technology, Gwangju, 2Section on Membrane Biology, Laboratory of Cellular and Molecular Biophysics, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, 3College of Pharmacy, Chung-Ang University, Seoul, 4Department of Bio-Materials, Graduate School and Department of Cellular & Molecular Medicine, School of Medicine, Chosun University, Gwangju 501-759, Korea Dermcidin is a human antibiotic peptide that is secreted by the of the modes of action of various antimicrobial peptides have sweat glands and has no homology to other known antimicro- revealed that their cationic nature contributes to their initial bial peptides. As an initial step toward understanding dermci- binding to negatively charged bacterial membranes through din’s mode of action at bacterial membranes, we used homo- electrostatic interaction, while their amphipathic structures en- nuclear and heteronuclear NMR to determine the conforma- hance peptide-lipid interactions at the water-bilayer interface, tion of the peptide in 50% trifluoroethanol solution. We found ultimately leading to cell death via pore formation or mem- that dermcidin adopts a flexible amphipathic α-helical struc- brane disintergration (9-14). ture with a helix-hinge-helix motif, which is a common molec- Dermcidin (DCD) is an antimicrobial peptide found in hu- ular fold among antimicrobial peptides. Spin-down assays of man sweat.
    [Show full text]
  • Peptides to Tackle Leishmaniasis: Current Status and Future Directions
    International Journal of Molecular Sciences Review Peptides to Tackle Leishmaniasis: Current Status and Future Directions Alberto A. Robles-Loaiza 1, Edgar A. Pinos-Tamayo 1, Bruno Mendes 2,Cátia Teixeira 3 , Cláudia Alves 3 , Paula Gomes 3 and José R. Almeida 1,* 1 Biomolecules Discovery Group, Universidad Regional Amazónica Ikiam, Tena 150150, Ecuador; [email protected] (A.A.R.-L.); [email protected] (E.A.P.-T.) 2 Departamento de Biologia Animal, Instituto de Biologia, Universidade Estadual de Campinas (UNICAMP), Campinas 13083-862, Brazil; [email protected] 3 LAQV-REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, 4169-007 Porto, Portugal; [email protected] (C.T.); [email protected] (C.A.); [email protected] (P.G.) * Correspondence: [email protected] Abstract: Peptide-based drugs are an attractive class of therapeutic agents, recently recognized by the pharmaceutical industry. These molecules are currently being used in the development of innovative therapies for diverse health conditions, including tropical diseases such as leishmaniasis. Despite its socioeconomic influence on public health, leishmaniasis remains long-neglected and categorized as a poverty-related disease, with limited treatment options. Peptides with antileishmanial effects encountered to date are a structurally heterogeneous group, which can be found in different natural sources—amphibians, reptiles, insects, bacteria, marine organisms, mammals, plants, and others—or inspired by natural toxins or proteins. This review details the biochemical and structural characteris- Citation: Robles-Loaiza, A.A.; tics of over one hundred peptides and their potential use as molecular frameworks for the design of Pinos-Tamayo, E.A.; Mendes, B.; antileishmanial drug leads.
    [Show full text]
  • Anticancer Potential of Bioactive Peptides from Animal Sources (Review)
    ONCOLOGY REPORTS 38: 637-651, 2017 Anticancer potential of bioactive peptides from animal sources (Review) LiNghoNg WaNg1*, CHAO DONG2*, XIAN LI1, WeNyaN haN1 and XIULAN SU1 1Clinical Medicine Research Center of the affiliated hospital, inner Mongolia Medical University; 2College of Basic Medicine of Inner Mongolia Medical University, Huimin, Hohhot, Inner Mongolia 010050, P.R. China Received October 10, 2016; Accepted April 10, 2017 DOI: 10.3892/or.2017.5778 Abstract. Cancer is the most common cause of human death 3. Mechanisms of action of bioactive peptides underlying worldwide. Conventional anticancer therapies, including their anticancer effects chemotherapy and radiation, are associated with severe side 4. Summary and perspective effects and toxicities as well as low specificity. Peptides are rapidly being developed as potential anticancer agents that specifically target cancer cells and are less toxic to normal 1. Introduction tissues, thus making them a better alternative for the preven- tion and management of cancer. Recent research has focused Although the rates of death due to cancer have been continu- on anticancer peptides from natural animal sources, such ously declining for the past 2 decades in developed nations, as terrestrial mammals, marine animals, amphibians, and cancer remains a major public health threat in many parts of animal venoms. However, the mode of action by which bioac- the world (1). The incidence of cancer in the developing world tive peptides inhibit the proliferation of cancer cells remains is currently increasing. Specifically, 55% of new cases arise unclear. In this review, we present the animal sources from in developing nations, a figure that could reach 60% by 2020 which bioactive peptides with anticancer activity are derived and 70% by 2050.
    [Show full text]
  • Evidence Supporting an Antimicrobial Origin of Targeting Peptides to Endosymbiotic Organelles
    cells Article Evidence Supporting an Antimicrobial Origin of Targeting Peptides to Endosymbiotic Organelles Clotilde Garrido y, Oliver D. Caspari y , Yves Choquet , Francis-André Wollman and Ingrid Lafontaine * UMR7141, Institut de Biologie Physico-Chimique (CNRS/Sorbonne Université), 13 Rue Pierre et Marie Curie, 75005 Paris, France; [email protected] (C.G.); [email protected] (O.D.C.); [email protected] (Y.C.); [email protected] (F.-A.W.) * Correspondence: [email protected] These authors contributed equally to this work. y Received: 19 June 2020; Accepted: 24 July 2020; Published: 28 July 2020 Abstract: Mitochondria and chloroplasts emerged from primary endosymbiosis. Most proteins of the endosymbiont were subsequently expressed in the nucleo-cytosol of the host and organelle-targeted via the acquisition of N-terminal presequences, whose evolutionary origin remains enigmatic. Using a quantitative assessment of their physico-chemical properties, we show that organelle targeting peptides, which are distinct from signal peptides targeting other subcellular compartments, group with a subset of antimicrobial peptides. We demonstrate that extant antimicrobial peptides target a fluorescent reporter to either the mitochondria or the chloroplast in the green alga Chlamydomonas reinhardtii and, conversely, that extant targeting peptides still display antimicrobial activity. Thus, we provide strong computational and functional evidence for an evolutionary link between organelle-targeting and antimicrobial peptides. Our results support the view that resistance of bacterial progenitors of organelles to the attack of host antimicrobial peptides has been instrumental in eukaryogenesis and in the emergence of photosynthetic eukaryotes. Keywords: Chlamydomonas; targeting peptides; antimicrobial peptides; primary endosymbiosis; import into organelles; chloroplast; mitochondrion 1.
    [Show full text]
  • Magainin 2 in Action: Distinct Modes of Membrane Permeabilization in Living Bacterial and Mammalian Cells
    Biophysical Journal Volume 95 December 2008 5757–5765 5757 Magainin 2 in Action: Distinct Modes of Membrane Permeabilization in Living Bacterial and Mammalian Cells Yuichi Imura, Naoki Choda, and Katsumi Matsuzaki Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-Ku, Kyoto 606-8501, Japan ABSTRACT Interactions of cationic antimicrobial peptides with living bacterial and mammalian cells are little understood, although model membranes have been used extensively to elucidate how peptides permeabilize membranes. In this study, the interaction of F5W-magainin 2 (GIGKWLHSAKKFGKAFVGEIMNS), an equipotent analogue of magainin 2 isolated from the African clawed frog Xenopus laevis, with unfixed Bacillus megaterium and Chinese hamster ovary (CHO)-K1 cells was investigated, using confocal laser scanning microscopy. A small amount of tetramethylrhodamine-labeled F5W-magainin 2 was incorporated into the unlabeled peptide for imaging. The influx of fluorescent markers of various sizes into the cytosol revealed that magainin 2 permeabilized bacterial and mammalian membranes in significantly different ways. The peptide formed pores with a diameter of ;2.8 nm (, 6.6 nm) in B. megaterium, and translocated into the cytosol. In contrast, the peptide significantly perturbed the membrane of CHO-K1 cells, permitting the entry of a large molecule (diameter, .23 nm) into the cytosol, accompanied by membrane budding and lipid flip-flop, mainly accumulating in mitochondria and nuclei. Adenosine triphosphate and negatively charged glycosaminoglycans were little involved in the magainin-induced permeabilization of membranes in CHO-K1 cells. Furthermore, the susceptibility of CHO-K1 cells to magainin was found to be similar to that of erythrocytes. Thus, the distinct membrane-permeabilizing processes of magainin 2 in bacterial and mammalian cells were, to the best of our knowledge, visualized and characterized in detail for the first time.
    [Show full text]
  • A Molecular Dynamics Study of the Bee Venom Melittin in Aqueous Solution, in Methanol, and Inserted in a Phospholipid Bilayer
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by RERO DOC Digital Library Eur Biophys J (2006) 35: 255–267 DOI 10.1007/s00249-005-0033-7 ARTICLE Alice Gla¨ttli Æ Indira Chandrasekhar Wilfred F. van. Gunsteren A molecular dynamics study of the bee venom melittin in aqueous solution, in methanol, and inserted in a phospholipid bilayer Received: 27 June 2005 / Revised: 5 October 2005 / Accepted: 8 October 2005 / Published online: 2 December 2005 Ó EBSA 2005 Abstract The structural properties of melittin, a small increase in membrane permeability through disruption amphipathic peptide found in the bee venom, are of the packing of lipid molecules, which is called the investigated in three different environments by molecu- ‘‘carpet effect’’ [6, 7]. However, they may also reorient to lar dynamics simulation. Long simulations have been adopt an orientation perpendicular to the bilayer sur- performed for monomeric melittin solvated in water, in face, a so-called transmembrane orientation, and then methanol, and shorter ones for melittin inserted in a associate to form either barrel-stave pores [8] or toroidal dimyristoylphosphatidylcholine bilayer. The resulting pores [9, 10] within the bilayer causing size-selective trajectories were analysed in terms of structural prop- leakage and eventually membrane-lysis [4, 11]. The erties of the peptide and compared to the available mode and effectiveness of the disruption of the mem- NMR data. While in water and methanol solution me- brane barrier function depends on the one hand on the littin is observed to partly unfold, the peptide retains its peptide concentration and on the other hand on the structure when embedded in a lipid bilayer.
    [Show full text]
  • (Amps) and Their Delivery Strategies for Wound Infections
    Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 17 July 2020 doi:10.20944/preprints202007.0375.v1 Peer-reviewed version available at Pharmaceutics 2020, 12, 840; doi:10.3390/pharmaceutics12090840 1 Review 2 An Update on Antimicrobial Peptides (AMPs) and 3 Their Delivery Strategies for Wound Infections 4 Viorica Patrulea 1,2,*, Gerrit Borchard 1,2 and Olivier Jordan 1,2,* 5 1 University of Geneva, Institute of Pharmaceutical Sciences of Western Switzerland, 1 Rue Michel Servet, 6 1211 Geneva, Switzerland 7 2 University of Geneva, Section of Pharmaceutical Sciences, 1 Rue Michel Servet, 1211 Geneva, Switzerland 8 * Correspondence: [email protected]; Tel.: +41-22379-3323 (V.P.); [email protected]; Tel.: +41- 9 22379-6586 (O.J.) 10 11 Abstract: Bacterial infections occur when wound healing fails to reach the final stage of healing, 12 usually hindered by the presence of different pathogens. Different topical antimicrobial agents are 13 used to inhibit bacterial growth due to antibiotic failure in reaching the infected site accompanied 14 very often by an increased drug resistance and other side effects. In this review, we focus on 15 antimicrobial peptides (AMPs), especially those with a high potential of efficacy against multidrug- 16 resistant and biofilm-forming bacteria and fungi present in wound infections. Currently, different 17 AMPs undergo preclinical and clinical phase to combat infection-related diseases. AMP dendrimers 18 (AMPDs) have been mentioned as potent microbial agents. Various AMP delivery strategies, such as 19 polymers, scaffolds, films and wound dressings, organic and inorganic nanoparticles, to combat 20 infection and modulate the healing rate have been discussed as well.
    [Show full text]
  • The Structure of the Antimicrobial Human Cathelicidin LL-37 Shows
    www.nature.com/scientificreports OPEN The structure of the antimicrobial human cathelicidin LL‑37 shows oligomerization and channel formation in the presence of membrane mimics Enea Sancho‑Vaello1,7, David Gil‑Carton2, Patrice François 3, Eve‑Julie Bonetti3, Mohamed Kreir4,8, Karunakar Reddy Pothula 5, Ulrich Kleinekathöfer 5 & Kornelius Zeth6* The human cathelicidin LL‑37 serves a critical role in the innate immune system defending bacterial infections. LL‑37 can interact with molecules of the cell wall and perforate cytoplasmic membranes resulting in bacterial cell death. To test the interactions of LL‑37 and bacterial cell wall components we crystallized LL‑37 in the presence of detergents and obtained the structure of a narrow tetrameric channel with a strongly charged core. The formation of a tetramer was further studied by cross‑ linking in the presence of detergents and lipids. Using planar lipid membranes a small but defned conductivity of this channel could be demonstrated. Molecular dynamic simulations underline the stability of this channel in membranes and demonstrate pathways for the passage of water molecules. Time lapse studies of E. coli cells treated with LL‑37 show membrane discontinuities in the outer membrane followed by cell wall damage and cell death. Collectively, our results open a venue to the understanding of a novel AMP killing mechanism and allows the rational design of LL‑37 derivatives with enhanced bactericidal activity. Te increase in antibiotic resistance is one of the biggest health challenges our society is currently facing1. As a consequence, the discovery of new bactericidal drug candidates from any source including antimicrobial peptides (AMPs) is urgent2–4.
    [Show full text]