Abstract
The spread of multidrug-resistant Gram-negative bacteria is an increasing threat to human health, because novel compound classes for the development of antibiotics have not been discovered for decades. Antimicrobial peptides (AMPs) may provide a much-needed breakthrough because these immunity-related defense molecules protect many eukaryotes against Gram-negative pathogens. Recent concepts in evolutionary immunology predict the presence of potent AMPs in insects that have adapted to survive in habitats with extreme microbial contamination. For example, the saprophagous and coprophagous maggots of the drone fly Eristalis tenax (Diptera) can flourish in polluted aquatic habitats, such as sewage tanks and farmyard liquid manure storage pits. We used next-generation sequencing to screen the E. tenax immunity-related transcriptome for AMPs that are synthesized in response to the injection of bacterial lipopolysaccharide. We identified 22 AMPs and selected nine for larger-scale synthesis to test their activity against a broad spectrum of pathogens, including multidrug-resistant Gram-negative bacteria. Two cecropin-like peptides (EtCec1-a and EtCec2-a) and a diptericin-like peptide (EtDip) displayed strong activity against the pathogens, even under simulated physiological conditions, and also achieved a good therapeutic window. Therefore, these AMPs could be used as leads for the development of novel antibiotics.
Highlights
The increasing prevalence of multidrug-resistant pathogens combined with the declining approval rate for new antibiotics has created an urgent need for novel compounds to fuel the drug development pipeline
We focused on a subset of five upregulated and one downregulated antimicrobial peptides (AMPs) for functional characterization, representing three of the four larger AMP families in E. tenax (Figures S1 and S2)
The increasing threat of multidrug-resistant bacteria and the lack of novel antibiotics in the development pipeline have encouraged the screening of AMPs to facilitate the discovery of alternative treatment options
Summary
The increasing prevalence of multidrug-resistant pathogens combined with the declining approval rate for new antibiotics has created an urgent need for novel compounds to fuel the drug development pipeline. The comparison of untreated maggots and those that were injected with bacterial lipopolysaccharide (LPS) to elicit a strong immune response revealed 22 transcripts encoding putative AMPs. For further analysis, we selected three cecropin-like peptides of the sarcotoxin subclass (EtCec, EtCec, and EtCec3), which feature a conserved C-terminal glycine residue that is thought to undergo post-translational amidation [8,9]. We selected three cecropin-like peptides of the sarcotoxin subclass (EtCec, EtCec, and EtCec3), which feature a conserved C-terminal glycine residue that is thought to undergo post-translational amidation [8,9] We synthesized both the non-amidated and amidated versions of each AMP (Table 1). These nine E. tenax AMPs were tested against an extended panel of Gram-negative clinical isolates in order to determine their toxicity, therapeutic potential, mode of action, and potential to confer selective pressure for resistance
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