Abstract
Current research in the field of antimicrobials is focused on developing novel antimicrobial agents to counteract the huge dilemma that the human population is mainly facing in regards to the rise of bacterial resistance and biofilm infections. Host defense peptides (HDPs) are a promising group of molecules for antimicrobial development as they display several attractive features suitable for antimicrobial activity, including their broad spectrum of activity and potency against bacteria. AamAP1 is a novel HDP that belongs to the venom of the North African scorpion Androctonus amoeruxi. In vitro antimicrobial assays revealed that the peptide displays moderate activity against Gram-positive and Gram-negative bacteria. Additionally, the peptide proved to be highly hemolytic and displayed significantly high toxicity against mammalian cells. In our study, a novel synthetic peptide analogue named A3 was synthetically modified from AamAP1 in order to enhance its activity and toxicity profile. The design strategy depended on modifying the amino acid sequence of AamAP1 in order to alter its net positive charge, percentage helicity and modify other parameters that are involved theoretically in HDPs activity. Accordingly, A3 was evaluated for its in vitro antimicrobial and anti-biofilm activity individually and in combination with four different types of conventional antibiotics against clinical isolates of multi-drug resistant (MDR) Gram-positive bacteria. A3 was also evaluated for its cytotoxicity against mammalian cells. A3 managed to selectively inhibit the growth of a wide range of resistant strains of Gram-positive bacteria. Our results also showed that combining A3 with conventional antibiotics caused a synergistic antimicrobial behavior that resulted in decreasing the MIC value for A3 peptide as low as 0.125 µM. At the concentrations needed to inhibit bacterial growth, A3 displayed minimal mammalian cell toxicity. In conclusion, A3 exhibits enhanced activity and selectivity when compared with the parent natural scorpion venom peptide. The combination of A3 with conventional antibiotics could provide researchers in the antimicrobial drug development field with a potential alternative for conventional antibiotics against MDR bacteria.
Highlights
Bacterial infectious diseases represent a major health problem currently facing humanity and threatening the proper and effective treatment of several infectious diseases that are mainly caused by pathogens that have acquired the ability to resist all types of conventional antibiotics currently found in the clinic [1]
Modification of the amino acid sequence of the scorpion venom peptide AamAP1 in order to increase its overall net positive charge along its helicity was the main objective of A3’s design strategy
Host defense peptides (HDPs) are considered one of the few promising groups that are currently available for development into effective antimicrobials to combat infections caused by resistant bacteria [22]
Summary
Bacterial infectious diseases represent a major health problem currently facing humanity and threatening the proper and effective treatment of several infectious diseases that are mainly caused by pathogens that have acquired the ability to resist all types of conventional antibiotics currently found in the clinic [1]. The misuse and overuse of antibiotics by health practitioners over the recent decades has contributed significantly to the issue of microbial resistance [3]. This sharp rise in antimicrobial resistance has been accompanied by a short supply of novel classes of antibiotics being developed and reaching the clinic [4]. One of the most notorious infectious causing bacteria includes Gram-positive bacteria such as the multidrug-resistant Staphylococcus aureus and the multidrug-resistant Enterococcus spp These pathogens are found in the hospital environment, and they exhibit a multidrug resistance mode of survival that complicates antimicrobial therapy. This continuous rise in antimicrobial resistance will lead to a major impact on the health of humans in addition to a huge barrier with health management costs and expenditure that will arise because of this dilemma [5]
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