Meucin-49, a multifunctional scorpion venom peptide with bactericidal synergy with neurotoxins

Abstract

Besides key roles in prey capture and predator defense, scorpion venom also functions as internal immune agents protecting the venom gland from infection and external immune agents cleaning saprophytic microbes from their own body surfaces. However, antimicrobials (typically antimicrobial peptides, AMPs) in the venom often exist in low abundance that might exclude their immune role alone, leaving an open question with regard to their in vivo biological function. Here, we report the bactericidal activity of seven peptides isolated from the scorpion Mesobuthus eupeus venom, including one classical α-helical AMP and five ion channel-targeted neurotoxins. This AMP of 49 amino acids (named Meucin-49) is a multifunctional molecule that displays a wide-spectrum and highly potent activity against Gram-positive and Gram-negative bacteria with strong hemotoxicity on scorpion's predators (i.e., mammals, lizards, and birds) and high insecticidal activity. Although the neurotoxins targeting voltage-gated sodium (Na) and/or large conductance calcium-activated potassium (BK) channels showed only marginal activity towards several species of bacteria, they were capable of significantly potentiating the bactericidal potency of Meucin-49. This observation highlights, for the first time, the venom's antibacterial immune function mediated by a joint action between neurotoxins and AMPs. The findings that traditionally defined neurotoxins possess (synergistic) bactericidal activity, while the classical AMPs play predatory and defensive roles, provide new evidence in favor of a general and intrinsic multifunctionality of scorpion venom components.

Adaptively evolved human oral actinomyces‐sourced defensins show therapeutic potential

“…An inhibition‐zone assay‐based method (Gao et al , 2018 ) was used to evaluate bactericidal synergy between AMSIN and HNP1&2 or lysozyme C. In this assay, AMSIN was set to a dose (nmol/well) at which only a small inhibition zone was visible and the latter was set to a dose (nmol/well) at which no inhibition zone was formed. Synergy was identified by the inhibition zone produced by the peptide combination significantly larger than that produced by AMSIN alone.…”

“…Despite intense studies over several decades, very few AMPs have reached to the stage of clinical applications to treat systemic infection (Fox, 2013 ; Zasloff, 2019 ; Magana et al , 2020 ). This frustration is mainly because of the intrinsic non‐specific cytotoxicity stemmed from their fundamental detergent‐like properties causing membrane (particularly erythrocytes) disruption, in a dose required for treatment (Gao et al , 2009 , 2018 ; Vaara, 2009 ; Mansour et al , 2014 ; Zasloff, 2019 ; Mahlapuu et al , 2020 ). In addition, human and other vertebrate‐derived AMPs often exhibit multifaceted modulating properties that can interfere with the human immune system function when used as systemically administered drugs (Vaara, 2009 ; Mansour et al , 2014 ; Zasloff, 2019 ).…”

Scorpion Venom: Detriments and Benefits

“…Recently, the spotlight has been put on the general and intrinsic multifunctionality of scorpion venom components, including AMPs [103]. For instance, native scorpion AMPs, UyCT3, and UyCT5 from U. yaschenkoi and an enhanced UyCT peptide (designated as D3) were demonstrated to be potential bioinsecticides and promising candidates for the engineering of aphid-resistant crops.…”

“…When pea aphids (Acyrthosiphon pisum) that are known as severe agricultural pests were fed with these AMPs, the AMPs displayed activity against aphid bacterial symbionts and reduced the number of symbionts, leading to a reduction in pest survival and delay in pest reproduction [111]. Meucin-49 from M. eupeus also showed insecticidal activity in addition to having broad-spectrum activity against Gram-positive and Gram-negative bacteria [103]. The red and blue benzoquinones from D. melici are multifunctional components that, besides showing antibacterial activity, also exert cytotoxic effects on neoplastic cell lines.…”

Structural characterization of scorpion peptides and their bactericidal activity against clinical isolates of multidrug-resistant bacteria

“…Scorpion AMPs also function as internal immune agents protecting the venom gland from infection and external immune agents cleaning saprophytic microbes from surface of scorpion body [5–7]. In addition, synergistic effects of antimicrobial scorpion peptide and neurotoxins against bacteria has been described, which provides further evidence in favor of multifunctionality of scorpion venom components [8]. Most of these antimicrobial peptides do not contain disulfide bridges in their structure, known as non-disulfide-bridged peptides (NDBP), and have been classified into several groups, such as scorpine-like, long, intermediate and short-chain AMPs [1,3].…”