US20090318382A1 - Use of bacterial polysaccharides for biofilm inhibition - Google Patents

Use of bacterial polysaccharides for biofilm inhibition Download PDF

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US20090318382A1
US20090318382A1 US12/307,045 US30704507A US2009318382A1 US 20090318382 A1 US20090318382 A1 US 20090318382A1 US 30704507 A US30704507 A US 30704507A US 2009318382 A1 US2009318382 A1 US 2009318382A1
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biofilm
bacterial
supernatant
cft073
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Jean-Marc Ghigo
Jaione Valle
Sandra Da Re
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Centre National de la Recherche Scientifique CNRS
Institut Pasteur de Lille
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Centre National de la Recherche Scientifique CNRS
Institut Pasteur de Lille
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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N63/00—Biocides, pest repellants or attractants, or plant growth regulators containing microorganisms, viruses, microbial fungi, animals or substances produced by, or obtained from, microorganisms, viruses, microbial fungi or animals, e.g. enzymes or fermentates
    • A01N63/20—Bacteria; Substances produced thereby or obtained therefrom
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
    • A01N25/08—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests containing solids as carriers or diluents
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/02—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms
    • A01N43/04—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom
    • A01N43/14—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom six-membered rings
    • A01N43/16—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom six-membered rings with oxygen as the ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A—HUMAN NECESSITIES
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    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A61L2/16—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor using chemical substances
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    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A61L2/16—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor using chemical substances
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    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/08—Materials for coatings
    • A61L29/085—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05D—PROCESSES FOR APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05D1/00—Processes for applying liquids or other fluent materials
    • B05D1/18—Processes for applying liquids or other fluent materials performed by dipping
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/23—Carbohydrates
    • A61L2300/232—Monosaccharides, disaccharides, polysaccharides, lipopolysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2420/00—Materials or methods for coatings medical devices
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2420/00—Materials or methods for coatings medical devices
    • A61L2420/02—Methods for coating medical devices
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention pertains to the field of biofilm prevention. More particularly, the invention provides novel components which can prevent and/or inhibit bacterial biofilm formation on various surfaces.
  • a biofilm is an accumulation of microorganisms embedded in a polysaccharide matrix and adherent to a biological or a non-biotic surface. Diverse microorganisms (bacteria, fungi, and/or protozoa, with associated bacteriophages and other viruses) can be found in these biofilms. Biofilms are ubiquitous in nature and are commonly found in a wide range of environments, including domestic and industrial water systems.
  • Biofilms are also etiologic agents for a number of disease states in mammals. Examples include infections of the oral soft tissues, teeth, middle ear, gastrointestinal tract, urogenital tract, airway/lung tissue, peritoneal membrane and eye. Biofilms also develop on medical indwelling devices, such as dental implants, urinary tract prostheses, peritoneal dialysis catheters, indwelling catheters for hemodialysis and for chronic administration of chemotherapeutic agents (Hickman catheters), cardiac implants such as pacemakers, prosthetic heart valves, ventricular assist devices (VAD), synthetic vascular grafts and stents, prostheses, internal fixation devices, percutaneous sutures, and tracheal and ventilator tubing.
  • medical indwelling devices such as dental implants, urinary tract prostheses, peritoneal dialysis catheters, indwelling catheters for hemodialysis and for chronic administration of chemotherapeutic agents (Hickman catheters), cardiac implants such as pacemakers, prosthetic heart valves
  • Biofilm development in industrial devices such as water systems or agri-food plants also raises safety problems.
  • Planktonic bacteria i.e., single-celled bacteria suspended in liquid media
  • bacteria in biofilms are far more resistant to antibiotics than their planktonic counterparts, and less accessible to the immune system.
  • conjugation occurs at a greater rate between cells in biofilms than between planktonic cells. This increased opportunity for gene transfer among bacteria is important, since bacteria resistant to antimicrobials or chemical biocides can transfer the genes for resistance to neighboring susceptible bacteria. Gene transfer can also convert a previous avirulent commensal organism into a highly virulent pathogen.
  • Biofilm formation is not limited to the attachment of bacteria to a surface. Indeed, when growing in depth, biofilm bacteria interact more between each other than with the actual physical substratum on which the biofilm initially developed. In a biofilm, bacteria can communicate through chemical signalling mechanisms, so that the community undergoes phenotypic changes when a minimum density (the quorum) is reached in the biofilm. This phenomenon, called “quorum sensing”, can be responsible for the expression of virulence factors.
  • E. coli biofilm-related polysaccharides such as colanic acid polymer, cellulose and (1-6) ⁇ -N-acetyl-glucosamine
  • E. coli isolates also produce two serotype-specific surface polysaccharides: the lipopolysaccharide (LPS) O antigen and capsular polysaceharide K antigen.
  • LPS lipopolysaccharide
  • capsular polysaceharide K antigen capsular polysaceharide K antigen.
  • the present invention provides a novel strategy for inhibiting biofilm formation, since the inventors have demonstrated, using in vitro mixed-species bacterial biofilm, that some bacteria release in the culture supernatant a soluble group II capsular polysaccharide that prevents biofilm formation by a wide range of Gram-negative and Gram-positive bacteria. As described in the experimental part below, these capsule components induce physico-chemical alterations of surface, leading to a reduction of cell-surface and cell-cell contacts that limits both initial adhesion and bacterial biofilm development.
  • a first object of the present invention is hence the use of a soluble group II-like capsular polysaccharide from a bacterial strain, for the preparation of a composition which prevents or inhibits adhesion of micro-organisms and/or biofilm development, in particular bacterial adhesion and/or bacterial biofilm development.
  • polysaccharide although used in the singular, can designate a mixture of different polysaccharides.
  • the capsular polysaccharides produced by the bacteria are indeed of various sizes.
  • E. coli capsules which constitute the outermost protective layer of the cell surface, are classified into four groups based on genetic and biosynthetic criteria.
  • Group II capsule is one of the 4 capsular types described in E.
  • Group II capsule displays a conserved modular genetic organization characterized by 3 functional regions. Region 1 (kpsFEDCUS) and region 3 (kpsMT) are conserved in all group II capsulated bacteria and encode proteins required for ABC-dependent export. Region 2 encodes a diversity of polysaccharidic structural components such as K1, K2 (CFT073), K5 and K96 capsular serotypes (Whitfield, 2006; Whitfield and Roberts, 1999). Group II-like capsules have also been described in Hemophilus influenzae and in Neisseria meningitides (Roberts, 1996).
  • a soluble group II-like capsular polysaccharide is obtained in the supernatant of a culture of bacteria selected amongst Escherichia coli, Hemophilus influenzae and Neisseria meningitidis .
  • group II-like capsular polysaccharides can designate capsular polysaccharides which are produced by other bacteria, provided they retain the anti-biofilm properties observed for the capsular polysaccharides produced by the above-mentioned strains.
  • capsular polysaccharides produced by the strain 47 of the ECOR collection are herein considered as a “group II-like capsular polysaccharide”, although this strain apparently produces a hybrid group II/group III capsule.
  • the present invention can be performed with polysaccharides having different purification levels.
  • the crude supernatant of a bacterial culture (separated from the bacteria by filter-sterilizing or centrifugation) can be used according to the invention as a composition comprising soluble group II-like capsular polysaccharides.
  • the soluble group II-like capsular polysaccharide can be obtained as a purified fraction. Three levels of purification are described in the experimental part below, as non-limitative examples.
  • a composition according to the invention can be obtained directly from the bacterial culture, for example after lysis of the bacteria.
  • compositions for inhibiting bacterial adhesion and/or bacterial biofilm development which comprises a soluble group II-like capsular polysaccharide from a bacterial strain.
  • a composition can comprise polysaccharides having different purification levels.
  • such a composition comprises a purified fraction of the supernatant of a culture of bacteria selected amongst E. coli, H. influenzae and N. meningitidis , comprising soluble group II-like capsular polysaccharides.
  • the present invention also relates to a process for purifying an anti-biofilm group II-like capsular polysaccharide from a bacterial strain, comprising the following steps:
  • the above process is preferably performed with a bacterial strain selected amongst E. coli, H. influenzae and N. meningitidis , more preferably with an uropathogenic E. coli.
  • step (i) can be carried out by centrifuging and/or filter-sterilizing the bacterial culture, in order to eliminate the bacterial cells.
  • tangential filtration can be performed without any preliminary centrifugation. Tangential filtration can be performed continuously.
  • step (ii) can be performed with three volumes of ethanol for one volume of supernatant.
  • the precipitate obtained in step (ii) is first resuspended in water, dialyzed against deionised water, and then lyophilized before step (iii).
  • the resuspension in step (iii) can be done in water or in any buffer suitable for the intended use.
  • An example of buffer which can be used is TrisHCl 20 mM, pH 7.5, with 25% propanol-1.
  • the anti-biofilm polysaccharides are obtained as a semi-purified product, which can be used as such according to the invention, especially in applications which do not need medical-grade products.
  • the purification process can comprise an additional step (iv) of purification by chromatography, especially ion exchange chromatography, for example using a DEAE-Sepharose column.
  • an optional centrifugation step can be performed between step (iii) and step (iv), to discard the insoluble fraction.
  • step (iv) can choose any appropriate buffer for performing step (iv).
  • buffer which can be used is TrisHCl 20 mM, pH 7.5, with 25% propanol-1.
  • the precipitate is resuspended in TrisHCl 20 mM, pH 7.5, with 25% propanol-1 in step (iii), and the column used in step (iv) is equilibrated with the same buffer.
  • the group II-like capsular polysaccharides can be eluted using a salt gradient, for example a NaCl gradient.
  • a salt gradient for example a NaCl gradient.
  • the group II-like capsular polysaccharides are eluted with 300 mM NaCl in TrisHCl 20 mM, pH 7.5, 25% propanol-1.
  • the soluble group II-like capsular polysaccharides obtained through a process as above-described can be used, according to the invention, for the preparation of a composition which prevents or inhibits bacterial adhesion and/or bacterial biofilm development.
  • An anti-biofilm composition comprising such purified polysaccharides is also part of the present invention.
  • composition of the present invention is formulated for preventive or therapeutic administration to a subject in need thereof.
  • compositions according to this aspect of the invention are oral solutions, solutions for infusion into the ear, collyrium, toothpaste or therapeutic dentifrice, etc. These compositions can be used, for example, to prevent the (re)-colonization of the gut, the lung, the ear, the sinus or any other organ or cavity, by pathogenic bacteria.
  • the composition according to the invention is a liquid or a paste, for example a paint, which can be applied on any kind surfaces in order to prevent biofilm formation on these surfaces.
  • an anti-biofilm coating comprising a group II-like capsular polysaccharide from a bacterial strain.
  • the group II-like capsular polysaccharide can have different purification levels, as described above.
  • the group II-like capsular polysaccharide is from a bacterial strain selected amongst Escherichia coli, Hemophilus influenzae and Neisseria meningitidis .
  • This coating can be obtained, for example, by application of a composition as above-described. It can also be in the form of sheets which can be applied on any kind of device on which biofilm formation must be avoided.
  • a medical or industrial device which is at least partly coated with an anti-biofilm coating comprising a group II-like capsular polysaccharide from a bacterial strain, is also part of the present invention.
  • Such an object can be obtained, for example, by dipping part of the device or the whole device, into a liquid composition as described above.
  • the skilled artisan can choose the incubation duration, depending on the material, the concentration of the composition in group II-like capsular polysaccharide, the intended use, and the like. Typically, said incubation can last from 10 seconds to 30 minutes. Short incubations ( ⁇ 1 to 5 minutes) are usually sufficient.
  • the coated device can then be sterilized by a variety of treatments, without damaging the coating. For example, it can be intensively washed and/or autoclaved. Any kind of device made of glass, pyrex, PVC, polycarbonate, polypropylene and the like, can advantageously be coated according to this aspect of the invention.
  • Non-limitative medical devices which can advantageously be coated according to this aspect of the invention are scalpels, burs and other non-disposable surgery and/or dentistry tools, and indwelling devices, such as dental implants, urinary tract prostheses, peritoneal dialysis catheters, indwelling catheters for hemodialysis and for chronic administration of chemotherapeutic agents (Hickman catheters), cardiac implants such as pacemakers, prosthetic heart valves, ventricular assist devices (VAD), synthetic vascular grafts and stents, prostheses, internal fixation devices, percutaneous sutures, and tracheal and ventilator tubing.
  • indwelling devices such as dental implants, urinary tract prostheses, peritoneal dialysis catheters, indwelling catheters for hemodialysis and for chronic administration of chemotherapeutic agents (Hickman catheters), cardiac implants such as pacemakers, prosthetic heart valves, ventricular assist devices (VAD), synthetic vascular grafts and stents, prostheses, internal
  • Non-limitative examples of industrial devices which can advantageously be coated according to this aspect of the invention are plumbing materials, such as pipes, tubes, valves and the like, air-cooled towers, warm water systems, coolant circuits of nuclear power plant, especially secondary and tertiary circuits, agri-food materials, such as silos, fermenters, colanders, etc., furniture elements such as lab tables, counter tops and the like, especially for clean rooms, etc.
  • plumbing materials such as pipes, tubes, valves and the like
  • air-cooled towers warm water systems
  • coolant circuits of nuclear power plant especially secondary and tertiary circuits
  • agri-food materials such as silos, fermenters, colanders, etc.
  • furniture elements such as lab tables, counter tops and the like, especially for clean rooms, etc.
  • FIG. 1 Biofilm inhibitory effect of CFT073.
  • A Biofilm formation of MG1655 F′ in microfermentors inoculated with 1 or 10 OD 600nm , equivalent of KS272 (grey) or CFT073 (black) cells.
  • MG1655F′ biofilm alone ⁇ , white. Results are average of 6 replicates ⁇ s.d. P ⁇ 0.001 compared with MG1655F′ biofilm.
  • B Microtiter plate MG1655F′ biofilm alone ( ⁇ ), or in the presence of KS272 or CFT073 supernatant, (S.KS272 and S.CFT073, respectively).
  • C MG1655F′ biofilm in microfermentors perfused with medium without supernatant ( ⁇ ) or with S.KS272 or S.CFT073.
  • D Growth curves of MG1655F′ alone ( ⁇ ) or with S.KS272 or S.CFT073.
  • E MG1655F′ cell viability alone ( ⁇ ) or with S.KS272 or S.CFT073 visualized with BacLight staining.
  • F Qualitative analysis of the biofilm formation in microtiter plate by different bacteria in the presence of CFT073 supernatant (S. CFT).
  • FIG. 2 Effect of CFT073 supernatant on Gram-positive and Gram-negative bacterial biofilm formation.
  • A Quantification of the microtiter plate biofilm formation of different bacteria, alone ( ⁇ ), with KS272 (S.KS) or CFT073 (S.CFT) supernatant. Levels of crystal violet retained were measured spectrophotometrically (OD 570nm ).
  • B Quantification of biofilm formed by several pathogenic bacteria in microfermentors using media not supplemented ( ⁇ ), or supplemented with S.CFT or S.KS. Error bars represent standard deviation of two independent experiments.
  • C Effect of CFT073 supernatant (S.CFT073) in mix biofilms of E.
  • E. faecalis E. faecalis
  • Supernatant of E. coli CFT073 ⁇ kpsD strain (S. ⁇ kpsD) that do not secrete any group II capsule is used as negative control.
  • D Qualitative analysis of biofilm formation of S. aureus and P. aeruginosa , in a microfermentor using media not supplemented, or supplemented with CFT073 supernatant.
  • FIG. 3 Relationship between capsule production and anti-biofilm activity of the CFT073 supernatant.
  • A Genetic organization of the CFT073 capsule R1, R2 and R3 regions. Genes with transposon insertions are marked with an asterisk.
  • B Biofilm formation of MG1655F′ cultivated in the presence of the capsule mutant supernatants.
  • C Hexose levels in the supernatants. kpsF, kpsU, c3692 and c3693 correspond to mutants that do not impair capsule production.
  • FIG. 4 Correlation between anti-biofilm activity and group II capsule. Biofilm formation of E. coli MG1655F′ and 1091 strains, and of the S. aureus 15981 strain cultured with: (A) supernatants of E. coli exhibiting anti-biofilm activity (see Table 1) (beside strain 47, all the strains tested produce group II capsule) (B) supernatants of CFT073, U-9, U-15 strains and their respective kpsD mutants.
  • FIG. 5 Anti-biofilm effect of Neisseria meningitides supernatant. Quantification of the microtiter plate biofilm formation of MG1655F′ in the presence of S. Neisseria . OD 570nm nm of the crystal violet dye was determined as described in (O'Toole and Kolter, 1998).
  • FIG. 6 Physico-chemical properties of the CFT073 supernatant.
  • a ⁇ potential of cationic colloids incubated with the dialyzed supernatants from: CFT073 (CFT), U-9, IHE3034 (IHE), EcoR72 (E-72) (dark grey) and their respective capsule mutants (light grey).
  • ⁇ correspond to M63B1glu treatment.
  • b Water droplet contact angle on surface incubated with CFT, U-9, IHE, E-72 (dark grey) and the capsule mutants (light grey).
  • c Propidium iodide adsorption onto cationic particles incubated with CFT, U-9, IHE, E-72, FR2 (CFT073 supernatant purified fraction), (dark grey) and their respective capsule mutants (light grey). The extent of the adsorption is given by the fluorescent intensity (>670 nm).
  • d Fluorescence microscopy of cationic particles incubated with CFT, S.CFT073 ⁇ l ( ⁇ R1), FR2 and not incubated ( ⁇ ). Error bars represent the standard deviation of the mean.
  • FIG. 7 Biofilm inhibition effect of CFT073 supernatant on coated surfaces. Biofilm formation in microfermentors by several bacteria using: untreated glass slides (upper panel), glass slides treated with CFT073 supernatant (middle panel) and glass slides treated with CFT073 ⁇ kpsD supernatant (lower panel).
  • FIG. 8 Impact of the treatment of spatula coated with S.CFT073 supernatant (S.CFT). Biofilm formation in microfermentors by MG1655F′ using untreated glass slides and glass slides treated with S.CFT or with boiled S.CFT, and then autoclaved or submitted to intensive wash.
  • S.CFT073 supernatant S.CFT073 supernatant
  • FIG. 9 CFT073 supernatant affects cell-cell interaction.
  • A MG1655F′ biofilm formation in microfermentors with media supplemented with CFT073 supernatant (S.CFT) at times 0 h, 1 h, 6 h (24 h of culture) and 24 h (48 h of culture).
  • S.CFT CFT073 supernatant
  • B GFP-tagged MG1655F′ inoculated in a flow-cell and monitored by confocal microscopy.
  • CFT073 or KS272 supernatants were supplemented after 3 h of culture and biofilms were grown for 12 h total.
  • FIG. 10 Anti-biofilm activity of the FR2 fraction.
  • CFT073 supernatant purified fraction (FR2) was added to the MG 1655F′ culture in concentrations ranging from 0.5 to 500 ⁇ g/ml. Biofilm formation of MG1655F′ was visualized after 24 h. Concentration of 50-100 ⁇ g/ml inhibited MG1655 F′ biofilm.
  • FIG. 11 Intestinal colonization by CFT073 and CFT073 ⁇ R1.
  • a Bars represent the standard error of the log 10 mean number of CFU per gram of feces; a Mann-Whitney test was used for statistical analysis, the level of statistical significance (*) was set at P values of ⁇ 0.016.
  • b Colon and caecium colonization by CFT073 (circles) and CFT073 ⁇ R1 (triangles).
  • DL Detection limit.
  • FIG. 12 Effect of growth phase and quorum-sensing in the anti-biofilm properties of CFT073 supernatant.
  • Bacterial strains are listed in Table 1 below. Gram-negative bacteria were grown at 37° C. in M63B1 minimal medium with 0.4% glucose (M63B1glu) or in LB rich medium. Gram-positive bacteria were grown in TSB with 0.25% glucose (TSBglu) at 37° C. The effect of CFT073 supernatant on bacterial growth and viability rate was evaluated using growth curve determination, colony forming unit count on LB plate and BacLight Live/Dead viability stain (Molecular Probes). Ferritin-staining and Scanning Electronic Microscopy was performed as described in (Bahrani-Mougeot et al., 2002). Epifluorescence and transmitted light microscopy were acquired using a Nikon E400 microscope. Autoaggregation assays were performed as described in (Beloin et al., 2006).
  • Le Bouguenec 1102 Commensal E. coli C.
  • Le Bouguenec 1103 Commensal E. coli C.
  • Le Bouguenec 1110 Commensal E. coli C.
  • Le Bouguenec 1125 Commensal E. coli C.
  • Le Bouguenec 1127 Commensal E. coli C.
  • aureus bovine mastitis subclinical isolate Cucarella et al., 2001
  • O-47 S. epidermidis clinical strain Heilmann et al., 1996) CH845 S. epidermidis clinical strain BM94314 (Galdbart et al., 2000) 54
  • E. faecalis clinical strain Toledo-Arana et al., 2001
  • 11279 E. faecalis clinical strain (Toledo-Arana et al., 2001) KP21 Klebsiella pneumoniae strain C.
  • Mixed biofilm cultures an 8 hours MG1655F′ biofilm formed in the internal microfermentors glass slide was infected with 1 OD 600nm equivalent of CFT073-gfp overnight culture. After 24 hours of continuous culture in M63B1glu, pictures of the glass slides were taken. Biofilm biomass was estimated by determining the OD 600nm of the resuspension of the biofilm formed on the internal glass slide (Ghigo, 2001).
  • Biofilm inhibition assays the incoming medium was mixed in a 1:1 ratio with filtered supernatants and brought into the microferrnentors at different time after bacteria inoculation (0, 1, 6 or 24 hours).
  • the biofilm was further cultivated for an additional 24 hours before biomass determination. Analysis of bacterial interaction with treated surfaces: the glass slides were incubated 1 min with filtered CFT073 supernatant and rinsed once in deionised water prior to inoculation in microfermentors. Biofilm formation on the slide was determined after 24 hours.
  • CFT073 supernatant active fraction, FR2 was purified using a DEAE-Sepharose column (Amersham) and eluted with 300 mM NaCl in 25% propanol-1, 20 mM TrisHCl pH7.5. Molecular weight of the polymer was estimated by gel filtration chromatography on Superdex-200 (Amersham) using dextran as standard. Polysaccharide degradations were done by total acid hydrolysis (trifluoroacetic acid, 4N, 4H, 100° C.) or by aqueous hydrofluoric acid (48% aq. HF, 2 days on water-ice).
  • Mariner transposon mutagenesis of E. coli CFT073 was performed as described in (Da Re and Ghigo, 2006).
  • the supernatants of 10,000 transposon mutants incubated 24 h, in LB at 37° C. in 96-well microtiter plates were extracted after centrifugation of the plates 15 min at 10000 rpm and their effect on MG1655F′ biofilm formation was analysed.
  • Transposon insertion sites were determined as described in (Da Re and Ghigo, 2006). Homology searches were performed using Blast 2.0. Deletion mutants were generated as detailed at http://www.pasteur.fr/recherche/unites/Ggb/3SPCRprotocol.html, using primers presented in Table 2.
  • Zeta potential was measured as in (Caruso et al., 1999) after 20 minutes of incubation of 10 ⁇ m in diameter cationic colloids latex particles with dialyzed precipitated supernatants (i.e., the level (ii) of purification indicated above).
  • the latex particles bear permanent net positive charge due to their polyethylenimine (PEI) coating.
  • the layer of PEI is a branched 6400 dalton molecular weight polymer bearing approximately 50% of methylated quaternary functions which confer a stable positive charge to the molecule. This polymer was deposited in aqueous phase on the initially carboxylated particles (Decher, 1997).
  • Hydrophilic properties of the supernatants were investigated by determining the contact angle formed by a 2.5 ⁇ l ultrapure water droplet with a glass plane surface previously incubated in the supernatants for 20 minutes. Surface interactions were analyzed by monitoring the adsorption of propidium iodide on supernatant-treated cationic colloids. The affinity of the treated surfaces for the fluorescent probe was tested using flow cytometry (Leboeuf and Henry, 2006) and fluorescence microscopy. All incubations of particles with supernatant were performed at low particle/volume fraction (ca. 0.2%) likely leading to surface saturation by the active species.
  • CFT073 and CFT073 ⁇ R1 in vivo colonization were performed as described previously (Maroncle et al., 2006). Mice were intragastrically fed with 1010 CFU. Bacteria contained in fecal samples were numbered on agar plates. For examination of bacterial growth in the host, mice were sacrificed at various times after inoculation; colon and caecum were homogenized in physiological water, and plated to determine cfu per gram of tissue.
  • CFT073 supernatant In order to determine the spectrum of the anti-biofilm activity of CFT073 supernatant, its effect was tested on several adherent bacteria ( E. coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Staphylococcus aureus, S. epidermidis and Enterococcus faecalis ). This analysis showed that CFT073 supernatant was active against a surprisingly wide range of bacteria, even in mixed cultures ( FIG. 1F and FIG. 2 ).
  • Region 2 is variable and encodes polysaccharide serotypes such as K1, K2 (CFT073), K5, K96 (Roberts, 1996).
  • the R1, R2 or R3 region, or each individual kps gene was deleted and it was observed that, except for kpsU, c3692 and c3693, all the mutants lost the ability to inhibit E. coli biofilm formation, which correlated with a reduced amount of precipitated sugars in the supernatant ( FIGS. 3B , 3 C). While a ferritin-stained capsule could still be detected around CFT073 cells ( FIG. 3D ), these results indicated that the CFT073 capsule nevertheless undergoes a significant release into the medium supernatant that is responsible for the observed anti-biofilm effect.
  • a biofilm formation inhibition test was also performed with a strain of Neisseria meningitidis , the capsule of which is biochemically very similar to the group II capsule of E. coli .
  • the results show that the supernatant of N. meningitidis also inhibits the biofilm formation of E. coli MG1655F′ ( FIG. 5 ), demonstrating that anti-biofilm activity is a property not only of the group II capsule from E. coli but also of capsules known to be similar to the latter (i.e., group II-like capsules).
  • the inventors monitored the adsorption of propidium iodide, a fluorescent amphiphillic cationic ion, on colloids coated with active or inactive supernatants. They first showed that anionic but inactive supernatant of the non-group II capsulated E. coli EcoR72 displayed strong affinity for the cationic fluorescent probe ( FIG. 6 c ). Despite their high negative charge, active supernatants displayed significantly lower probe affinity than inactive but less negatively charged capsule mutant supernatants ( FIGS. 6 c and 6 d ).
  • the anti-biofilm effect of the CFT073 supernatant persisted even after drastic treatments of the glass slide ( FIG. 8 ), which suggests that the group II capsule could be used in applications which necessitate a sterilisation step (such as agro-industrial or medical applications).
  • the anti-biofilm activity of different concentrations of the FR2 fraction was tested in microtiter plate assays. This showed that the purified FR2 fraction is active at concentrations starting from 50 ⁇ g/ml ( FIG. 10 ).
  • group II-like capsular polysaccharides are released in the culture supernatant and display anti-adhesion properties against a wide range of bacteria, including important nosocomial pathogens.
  • This study reveals a novel property of the group II capsular polysaccharides that are commonly expressed by extra-intestinal E. coli , but also by other pathogens such as Neisseria meningitides (Kaijser, 1973; Sandberg et al., 1988), which supernatant could also inhibit E. coli biofilm formation (data not shown).
  • Group II capsule has been shown to be involved in UPEC virulence by increasing their resistance to phagocytosis and to the bactericidal effects of human serum (Cross et al., 1986; Kaper et al., 2004; Pluschke et al., 1983; Russo et al., 1995). Capsule could also play an important biological role in UPEC interactions with living and inert surfaces. In particular, besides bacterial competition, the inhibition of UPEC own adhesion by group II capsule secretion may contribute to gastrointestinal tract colonisation by reducing bacteria-bacteria interactions (Schembri et al., 2004), thus avoiding bacterial clearance due to clump formation (Favre-Bonte et al., 1999). Consistently, it was observed that an uncapsulated CFT073 ⁇ R1 mutant is unable to colonize the mouse intestine ( FIG. 11 ).

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US10900043B2 (en) 2014-09-02 2021-01-26 Arizona Board Of Regents On Behalf Of The University Of Arizona Compositions and methods for treating bacterial disease
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US9603977B2 (en) * 2006-06-30 2017-03-28 Institut Pasteur Use of bacterial polysaccharides for biofilm inhibition
US11452291B2 (en) 2007-05-14 2022-09-27 The Research Foundation for the State University Induction of a physiological dispersion response in bacterial cells in a biofilm
WO2014173059A1 (zh) * 2013-04-24 2014-10-30 启东盖天力药业有限公司 一种槐耳多糖蛋白及其制备方法和用途
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