The proline-rich peptide Bac7(1-35) reduces mortality from Salmonella typhimurium in a mouse model of infection

Abstract

BackgroundBac7 is a proline-rich peptide with a potent in vitro antimicrobial activity against Gram-negative bacteria. Here we investigated its activity in biological fluids and in vivo using a mouse model of S. typhimurium infection.ResultsThe efficacy of the active 1-35 fragment of Bac7 was assayed in serum and plasma, and its stability in biological fluids analyzed by Western blot and mass spectrometry. The ability of the peptide to protect mice against Salmonella was assayed in a typhoid fever model of infection by determination of survival rates and bacterial load in liver and spleen of infected animals. In addition, the peptide's biodistribution was evaluated by using time-domain optical imaging. Bac7(1-35) retained a substantial in vivo activity showing a very low toxicity. The peptide increased significantly the number of survivors and the mean survival times of treated mice reducing the bacterial load in their organs despite its rapid clearance.ConclusionsOur results provide a first indication for a potential development of Bac7-based drugs in the treatment of salmonellosis and, eventually, other Gram-negative infections. The in vivo activity for this peptide might be substantially enhanced by decreasing its excretion rate or modifying the treatment schedule.

Novel Apidaecin 1b Analogs with Superior Serum Stabilities for Treatment of Infections by Gram-Negative Pathogens

“…S1), which points to the C-terminally truncated peptides [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] Api88 and 1-16 Api88, respectively. The peak area of [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] Api88 increased very rapidly during the first 30 min to 70% of the initial peak area of Api88 and then showed a further slight increase to 80% within the next 30 min, before decreasing slowly afterwards (Fig. 1A).…”

“…All these studies have confirmed a very low toxicity in mice and high efficacies in different murine infection models, with peptide doses typically below 10 mg/kg of body weight (BW) (8,18). Recently, we were able to extend the activity of apidaecin 1b, an 18-residue-long PrAMP expressed in honey bees, toward K. pneu-moniae and P. aeruginosa, by modifying two residues and both termini (19).…”

“…Proline-rich AMPs (PrAMPs) represent an important class of peptides that act by a different, completely nonlytic mechanism, mostly on Gram-negative bacteria, such as Enterobacteriaceae (e.g., Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae) and nonfermenting species (e.g., Acinetobacter baumannii and Pseudomonas aeruginosa) (7). These peptides contain a high content of proline (ϳ30%) and arginine residues and are typically 40 to 60 residues long in mammals (8,9). Insects express shorter PrAMPs, typically around 20 residues long (10).…”

Importance of Endosomal Cathelicidin Degradation To Enhance DNA-Induced Chicken Macrophage Activation

“…Their importance in innate host defense has been clearly demonstrated in several in vivo knockout models, where loss of HDP expression was shown to result in an increased susceptibility to infections (4)(5)(6). In addition, administration of HDPs was shown to have a protective effect in multiple in vivo infection models (7)(8)(9). Because of this strong protective activity, therapeutic use of HDPs as anti-infectives has gained great interest in both human and veterinary medicine (10).…”

Intracellular Toxicity of Proline-Rich Antimicrobial Peptides Shuttled into Mammalian Cells by the Cell-Penetrating Peptide Penetratin

“…Insect-derived PrAMPs, e.g., abaecin, apidaecin, drosocin, and pyrrhocoricin (4,5,7,23), are typically 20 to 35 residues long and have a relatively high proportion of basic amino acid residues. Recently, several laboratories have started to optimize PrAMPs for clinical applications, e.g., A3-APO (25), Bac7 (12), oncocin (16), and Api88 (9), which proved successful in rodent infection models (1,15,32). Mechanistically, PrAMPs and the related designer peptides enter the bacteria and kill them, most likely by inhibiting the 70-kDa bacterial chaperone DnaK (17,20,24).…”