Improving the Activity and Selectivity of a Scorpion-Derived Peptide, A3a, against Acinetobacter baumannii through Rational Design

被引:0
作者
Moller, Dalton S. [1 ]
van der Walt, Mandelie [1 ]
Oosthuizen, Carel [2 ]
Serian, Miruna [3 ]
Serem, June C. [4 ]
Lorenz, Christian D. [5 ]
Mason, A. James [6 ]
Bester, Megan J. [4 ]
Gaspar, Anabella R. M. [1 ]
机构
[1] Univ Pretoria, Fac Nat & Agr Sci, Dept Biochem Genet & Microbiol, ZA-0002 Pretoria, South Africa
[2] Univ Cape Town, Drug Discovery & Dev Ctr H3D, ZA-7701 Rondebosch, South Africa
[3] Kings Coll London, Fac Nat Math & Engn Sci, Dept Phys, London WC2R 2LS, England
[4] Univ Pretoria, Fac Hlth Sci, Dept Anat, ZA-0002 Pretoria, South Africa
[5] Kings Coll London, Fac Nat Math & Engn Sci, Dept Engn, London WC2R 2LS, England
[6] Kings Coll London, Fac Life Sci & Med, Sch Canc & Pharmaceut Sci, Inst Pharmaceut Sci, London SE1 9NH, England
来源
ACS OMEGA | 2025年 / 10卷 / 05期
基金
英国工程与自然科学研究理事会; 英国医学研究理事会; 英国生物技术与生命科学研究理事会;
关键词
HELICAL ANTIMICROBIAL PEPTIDES; MEMBRANE INTERACTION; SECONDARY STRUCTURE; TRYPTOPHAN; RESISTANCE; AMIDATION; RESIDUES; DYNAMICS; ANALOGS; CHARGE;
D O I
暂无
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
The rise in antimicrobial resistance has led to an increased desire to understand how antimicrobial peptides (AMPs) can be better engineered to kill antibiotic-resistant bacteria. Previously, we showed that C-terminal amidation of a peptide, identified in scorpion Androctonus amoreuxi venom, increased its activity against both Gram-positive and -negative bacteria. Here, we incorporate all-atom molecular dynamics (MD) simulations in a rational design strategy to create analogues of A3a with greater therapeutic potential. We discover two novel AMPs which achieve greater potency against, and selectivity toward, Acinetobacter baumannii ATCC 19606 but via two distinct mechanisms and which are effective in Galleria mellonella models of A. baumannii burn wound infection. While CD spectroscopy indicates A3a adopts an alpha-helix conformation in the presence of models of the Gram-negative bacterial plasma membrane, MD simulations reveal it adopts a hairpin conformation during initial binding. Three different strategies, designed to stabilize this hairpin conformation, produce substantially different outcomes. Deletion of Ile6 and Ile10 restricts conformational flexibility, characteristic of A3a, during membrane binding, prevents adoption of the alpha-helix conformation in the steady state, and abrogates the antibacterial activity. In contrast, substitution of arginine 7 to lysine (A3a[R7K]) or isoleucine 14 to tryptophan (A3a[I14W]) does not consistently affect peptide conformations. Both of these new analogues are rapidly bactericidal toward A. baumannii ATCC 19606 but A3a[R7K] also causes rapid permeabilization and while the antibacterial potency and selectivity are increased for both peptides, this is greatest for A3a[I14W]. Integration of atomistic MD simulations into a multidisciplinary approach to understanding antimicrobial peptide mechanism of action is a valuable tool for interpreting the effects of rational design strategies.
引用
收藏
页码:4699 / 4710
页数:12
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