title: A High-Affinity Native Human Antibody Disrupts Biofilm from Staphylococcus aureus Bacteria and Potentiates Antibiotic Efficacy in a Mouse Implant Infection Model.
abstract: Many serious bacterial infections are difficult to treat due to biofilm formation, which provides physical protection and induces a sessile phenotype refractory to antibiotic treatment compared to the planktonic state. A key structural component of biofilm is extracellular DNA, which is held in place by secreted bacterial proteins from the DNABII family: integration host factor (IHF) and histone-like (HU) proteins. A native human monoclonal antibody, TRL1068, has been discovered using single B-lymphocyte screening technology. It has low-picomolar affinity against DNABII homologs from important Gram-positive and Gram-negative bacterial pathogens. The disruption of established biofilm was observedin vitroat an antibody concentration of 1.2 μg/ml over 12 h. The effect of TRL1068in vivowas evaluated in a murine tissue cage infection model in which a biofilm is formed by infection with methicillin-resistantStaphylococcus aureus(MRSA; ATCC 43300). Treatment of the established biofilm by combination therapy of TRL1068 (15 mg/kg of body weight, intraperitoneal [i.p.] administration) with daptomycin (50 mg/kg, i.p.) significantly reduced adherent bacterial count compared to that after daptomycin treatment alone, accompanied by significant reduction in planktonic bacterial numbers. The quantification of TRL1068 in sample matrices showed substantial penetration of TRL1068 from serum into the cage interior. TRL1068 is a clinical candidate for combination treatment with standard-of-care antibiotics to overcome the drug-refractory state associated with biofilm formation, with potential utility for a broad spectrum of difficult-to-treat bacterial infections.
authors.affiliation: Trellis Bioscience, LLC, Menlo Park, California, USA.
authors.forename: Angeles
authors.initials: A
authors.lastname: Estellés
authors.affiliation: Infection Biology Laboratory, Department of Biomedicine, University Hospital of Basel, Basel, Switzerland.
authors.forename: Anne-Kathrin
authors.initials: AK
authors.lastname: Woischnig
authors.affiliation: Trellis Bioscience, LLC, Menlo Park, California, USA.
authors.forename: Keyi
authors.initials: K
authors.lastname: Liu
authors.affiliation: Trellis Bioscience, LLC, Menlo Park, California, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Stephenson
authors.affiliation: Trellis Bioscience, LLC, Menlo Park, California, USA.
authors.forename: Evelene
authors.initials: E
authors.lastname: Lomongsod
authors.affiliation: Trellis Bioscience, LLC, Menlo Park, California, USA.
authors.forename: Da
authors.initials: D
authors.lastname: Nguyen
authors.affiliation: Trellis Bioscience, LLC, Menlo Park, California, USA.
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Trellis Bioscience, LLC, Menlo Park, California, USA.
authors.forename: Manfred
authors.initials: M
authors.lastname: Heidecker
authors.affiliation: Trellis Bioscience, LLC, Menlo Park, California, USA.
authors.forename: Yifan
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Trellis Bioscience, LLC, Menlo Park, California, USA.
authors.forename: Reyna J
authors.initials: RJ
authors.lastname: Simon
authors.affiliation: Trellis Bioscience, LLC, Menlo Park, California, USA.
authors.forename: Edgar
authors.initials: E
authors.lastname: Tenorio
authors.affiliation: Trellis Bioscience, LLC, Menlo Park, California, USA.
authors.forename: Stote
authors.initials: S
authors.lastname: Ellsworth
authors.affiliation: Trellis Bioscience, LLC, Menlo Park, California, USA.
authors.forename: Anton
authors.initials: A
authors.lastname: Leighton
authors.affiliation: Trellis Bioscience, LLC, Menlo Park, California, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Ryser
authors.affiliation: Infection Biology Laboratory, Department of Biomedicine, University Hospital of Basel, Basel, Switzerland Division of Infectious Diseases and Hospital Epidemiology, University Hospital of Basel, Basel, Switzerland.
authors.forename: Nina Khanna
authors.initials: NK
authors.lastname: Gremmelmaier
authors.affiliation: Trellis Bioscience, LLC, Menlo Park, California, USA lkauvar@trellisbio.com.
authors.forename: Lawrence M
authors.initials: LM
authors.lastname: Kauvar
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000900:Anti-Bacterial Agents / Q000096:biosynthesis / Q000302:isolation & purification / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000096:biosynthesis / Q000302:isolation & purification / Q000494:pharmacology*; D000918:Antibody Specificity; D001402:B-Lymphocytes / Q000737:chemistry / Q000166:cytology / Q000276:immunology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D018441:Biofilms / Q000187:drug effects* / Q000254:growth & development; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D017576:Daptomycin / Q000494:pharmacology; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D018604:Epitope Mapping; D005260:Female; D005547:Foreign Bodies / Q000188:drug therapy* / Q000382:microbiology; D015870:Gene Expression; D007274:Injections, Intraperitoneal; D034982:Integration Host Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D010933:Plankton / Q000187:drug effects / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D016415:Sequence Alignment; D059010:Single-Cell Analysis; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000382:microbiology
chemical_list: D000900:Anti-Bacterial Agents; D000911:Antibodies, Monoclonal; D001426:Bacterial Proteins; D004268:DNA-Binding Proteins; C075779:Hbsu protein, bacteria; D034982:Integration Host Factors; D017576:Daptomycin
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