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- Title
Profiling antimicrobial peptides from the medical maggot Lucilia sericata as potential antibiotics for MDR Gram-negative bacteria.
- Authors
Hirsch, Rolf; Wiesner, Jochen; Marker, Alexander; Pfeifer, Yvonne; Bauer, Armin; Hammann, Peter E; Vilcinskas, Andreas
- Abstract
Background The ability of MDR Gram-negative bacteria to evade even antibiotics of last resort is a severe global challenge. The development pipeline for conventional antibiotics cannot address this issue, but antimicrobial peptides (AMPs) offer an alternative solution. Objectives Two insect-derived AMPs (LS-sarcotoxin and LS-stomoxyn) were profiled to assess their suitability for systemic application in humans. Methods The peptides were tested against an extended panel of 114 clinical MDR Gram-negative bacterial isolates followed by time–kill analysis, interaction studies and assays to determine the likelihood of emerging resistance. In further in vitro studies we addressed cytotoxicity, cardiotoxicity and off-target interactions. In addition, an in vivo tolerability and pharmacokinetic study in mice was performed. Results LS-sarcotoxin and LS-stomoxyn showed potent and selective activity against Gram-negative bacteria and no cross-resistance with carbapenems, fluoroquinolones or aminoglycosides. Peptide concentrations of 4 or 8 mg/L inhibited 90% of the clinical MDR isolates of Escherichia coli, Enterobacter cloacae, Acinetobacter baumannii and Salmonella enterica isolates tested. The ' all - d ' homologues of the peptides displayed markedly reduced activity, indicating a chiral target. Pharmacological profiling revealed a good in vitro therapeutic index, no cytotoxicity or cardiotoxicity, an inconspicuous broad-panel off-target profile, and no acute toxicity in mice at 10 mg/kg. In mouse pharmacokinetic experiments LS-sarcotoxin and LS-stomoxyn plasma levels above the lower limit of quantification (1 and 0.25 mg/mL, respectively) were detected after 5 and 15 min, respectively. Conclusions LS-sarcotoxin and LS-stomoxyn are suitable as lead candidates for the development of novel antibiotics; however, their pharmacokinetic properties need to be improved for systemic administration.
- Subjects
ANTI-infective agents; ANTIMICROBIAL peptides; ACINETOBACTER baumannii; ESCHERICHIA coli growth; TREATMENT of escherichia coli diseases
- Publication
Journal of Antimicrobial Chemotherapy (JAC), 2019, Vol 74, Issue 1, p96
- ISSN
0305-7453
- Publication type
Article
- DOI
10.1093/jac/dky386