In the past century, antimicrobial drugs revolutionized the control of diseases caused by microorganisms, such as bacteria, fungi, viruses, and parasites. However, due to the global problem of antimicrobial resistance (AMR) development, new antimicrobial agents are crucially needed for the 21st century. These agents must be discovered at a rate that is sufficiently fast to combat the evolving rate of multidrug resistance (MDR) in microorganisms
[11]. Natural product research holds promise for providing new molecules as a basis for novel antimicrobial drug development. In 1991, it was reported that the folding pattern of charybdotoxin, a KTx isolated from
L. quinquestriatus hebraeus venom, was strikingly similar to that of the insect antibacterial component, defensin
[12]. This discovery set the stage for studies on scorpion-derived antimicrobial peptides (AMPs), which have led to a large number of discoveries that may be of relevance for therapeutic applications. 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), which are known as severe agricultural pests, were fed with UyCT3 and UyCT5, the number of aphid bacterial symbionts reduced which led to a reduction in pest survival and a delay in pest reproduction
[13]. Meucin-49 from
M. eupeus also showed insecticidal activity in addition to having broad-spectrum activity against Gram-positive and Gram-negative bacteria
[14]. The red and blue benzoquinones from
D. melici are multifunctional components that, besides showing antibacterial activity, also exert cytotoxic effects on neoplastic cell lines. In mouse models of MDR tuberculosis infection, blue benzoquinone showed comparable activity to commercially available antibiotics, while it did not cause adverse side effects in healthy mice
[15]. Similarly, the low molecular mass chitosan obtained from
M. gibbosus had a strong inhibitory effect against the bacterium
L. monocytogenes and the yeast
C. albicans. In addition, its antibacterial activity against
B. subtilis and
S. enteritidis was higher than the antibiotic, gentamicin
[16]. However, despite the desirable potent action against microbes, natural scorpion AMPs generally have cytotoxic effects on eukaryotic cells, which is an obstacle that must be overcome. To this end, protein engineering techniques have been used to improve the potency and spectra of antimicrobial activity of the natural scorpion AMPs
[17][18][19]. Employing these techniques, it has been demonstrated that scorpion AMPs can be effectively used as scaffolds to design more specific and less harmful antibiotics
[20][21]. In addition, combining low concentrations of fast-killing scorpion AMPs with classical antibiotics is another approach that can be pursued in order to circumvent their cytotoxic effects against eukaryotic cells
[22]. All in all, using natural scorpion AMPs as scaffolds for the rational design of novel antimicrobial agents and mixed formulations of antibiotics opens a new window of research to be pursued in the future.