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Profiling antimicrobial peptides from the medical maggot Lucilia sericata as potential antibiotics for MDR
Rolf Hirsch1, Jochen Wiesner1, Alexander Marker2
1Fraunhofer Institute for Molecular Biology and Applied Ecology, Department of Bioresources, Gießen, Germany.
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.
Insights
Two insect-derived antimicrobial peptides (AMPs), LS-sarcotoxin and LS-stomoxyn, show potent activity against multidrug-resistant Gram-negative bacteria. While effective, their pharmacokinetic properties require enhancement for systemic human use.
Area of Science:
- Microbiology
- Pharmacology
- Drug Discovery
Background:
- Multidrug-resistant (MDR) Gram-negative bacteria pose a significant global health threat, evading current antibiotics.
- Conventional antibiotic development faces challenges, necessitating alternative therapeutic strategies like antimicrobial peptides (AMPs).
Purpose of the Study:
- To evaluate two insect-derived antimicrobial peptides (AMPs), LS-sarcotoxin and LS-stomoxyn, for their potential as systemic human antibiotics.
- To assess the efficacy, safety, and resistance potential of these AMPs against clinical MDR Gram-negative bacterial isolates.
Main Methods:
- Tested LS-sarcotoxin and LS-stomoxyn against 114 clinical MDR Gram-negative bacterial isolates.
- Conducted time-kill assays, interaction studies, and resistance emergence assays.
- Performed in vitro cytotoxicity, cardiotoxicity, and off-target interaction studies, alongside in vivo tolerability and pharmacokinetic studies in mice.
Main Results:
- Both peptides demonstrated potent, selective activity against Gram-negative bacteria with no cross-resistance to existing antibiotic classes.
- Effective inhibition of 90% of tested MDR isolates (e.g., E. coli, A. baumannii) at 4-8 mg/L.
- Showed a good in vitro therapeutic index, no significant cytotoxicity or cardiotoxicity, and no acute toxicity in mice at 10 mg/kg.
Conclusions:
- LS-sarcotoxin and LS-stomoxyn are promising lead candidates for novel antibiotic development against MDR Gram-negative pathogens.
- Further optimization of pharmacokinetic properties is necessary for successful systemic administration in humans.
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