title: In vitro and in vivo efficacy, toxicity, bio-distribution and resistance selection of a novel antibacterial drug candidate.
abstract: A synthetic antimicrobial peptide was identified as a possible candidate for the development of a new antibacterial drug. The peptide, SET-M33L, showed a MIC90 below 1.5 μM and 3 μM for Pseudomonas aeruginosa and Klebsiella pneumoniae, respectively. In in vivo models of P. aeruginosa infections, the peptide and its pegylated form (SET-M33L-PEG) enabled a survival percentage of 60-80% in sepsis and lung infections when injected twice i.v. at 5 mg/Kg, and completely healed skin infections when administered topically. Plasma clearance showed different kinetics for SET-M33L and SET-M33L-PEG, the latter having greater persistence two hours after injection. Bio-distribution in organs did not show significant differences in uptake of the two peptides. Unlike colistin, SET-M33L did not select resistant mutants in bacterial cultures and also proved non genotoxic and to have much lower in vivo toxicity than antimicrobial peptides already used in clinical practice. The characterizations reported here are part of a preclinical development plan that should bring the molecule to clinical trial in the next few years.
authors.affiliation: Department of Medical Biotechnologies, University of Siena, Siena, Italy.
authors.forename: Jlenia
authors.initials: J
authors.lastname: Brunetti
authors.affiliation: SetLance srl, via Fiorentina 1, Siena, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Falciani
authors.affiliation: Department of Medical Biotechnologies, University of Siena, Siena, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Roscia
authors.affiliation: Department of Medical Biotechnologies, University of Siena, Siena, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Pollini
authors.affiliation: Department of Medical Biotechnologies, University of Siena, Siena, Italy.|Clinical Pathology Laboratory, Azienda Ospedaliera Universitaria Senese, Policlinico Le Scotte, viale Bracci, Siena, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Bindi
authors.affiliation: Department of Medical Biotechnologies, University of Siena, Siena, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Scali
authors.affiliation: Radiochemistry and Nuclear Imaging Group CIC biomaGUNE, San Sebastián, Spain.
authors.forename: Unai Cossio
authors.initials: UC
authors.lastname: Arrieta
authors.affiliation: Radiochemistry and Nuclear Imaging Group CIC biomaGUNE, San Sebastián, Spain.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Gómez-Vallejo
authors.affiliation: Department of Medical Biotechnologies, University of Siena, Siena, Italy.
authors.forename: Leila
authors.initials: L
authors.lastname: Quercini
authors.affiliation: Department of Medical Biotechnologies, University of Siena, Siena, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Ibba
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Prato
authors.affiliation: Department of Medical Biotechnologies, University of Siena, Siena, Italy.|Department of Experimental and Clinical Medicine, University of Florence, Italy.|Microbiology and Virology Unit, Florence Careggi University Hospital, Florence, Italy.|Don Carlo Gnocchi Foundation I.R.C.C.S., Florence, Italy.
authors.forename: Gian Maria
authors.initials: GM
authors.lastname: Rossolini
authors.affiliation: Radiochemistry and Nuclear Imaging Group CIC biomaGUNE, San Sebastián, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Llop
authors.affiliation: Department of Medical Biotechnologies, University of Siena, Siena, Italy.|Clinical Pathology Laboratory, Azienda Ospedaliera Universitaria Senese, Policlinico Le Scotte, viale Bracci, Siena, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Bracci
authors.affiliation: Department of Medical Biotechnologies, University of Siena, Siena, Italy.|Clinical Pathology Laboratory, Azienda Ospedaliera Universitaria Senese, Policlinico Le Scotte, viale Bracci, Siena, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Pini
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry / Q000627:therapeutic use*; D003091:Colistin / Q000627:therapeutic use; D004195:Disease Models, Animal; D024881:Drug Resistance, Bacterial; D005260:Female; D006801:Humans; D007711:Klebsiella pneumoniae / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011014:Pneumonia / Q000188:drug therapy*; D011092:Polyethylene Glycols / Q000737:chemistry; D011552:Pseudomonas Infections / Q000188:drug therapy*; D011550:Pseudomonas aeruginosa / Q000502:physiology*; D018805:Sepsis / Q000188:drug therapy*; D012867:Skin / Q000187:drug effects* / Q000382:microbiology / Q000473:pathology
chemical_list: D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D011092:Polyethylene Glycols; D003091:Colistin