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Ab initio design of potent anti-MRSA peptides based on database filtering technology.

ABSTRACT: To meet the challenge of antibiotic resistance worldwide, a new generation of antimicrobials must be developed. This communication demonstrates ab initio design of potent peptides against methicillin-resistant Staphylococcus aureus (MRSA). Our idea is that the peptide is very likely to be active when the most probable parameters are utilized in each step of the design. We derived the most probable parameters (e.g., amino acid composition, peptide hydrophobic content, and net charge) from the antimicrobial peptide database by developing a database filtering technology (DFT). Different from classic cationic antimicrobial peptides usually with high cationicity, DFTamP1, the first anti-MRSA peptide designed using this technology, is a short peptide with high hydrophobicity but low cationicity. Such a molecular design made the peptide highly potent. Indeed, the peptide caused bacterial surface damage and killed community-associated MRSA USA300 in 60 min. Structural determination of DFTamP1 by NMR spectroscopy revealed a broad hydrophobic surface, providing a basis for its potency against MRSA known to deploy positively charged moieties on the surface as a mechanism for resistance. Our ab initio design combined with database screening led to yet another peptide with enhanced potency. Because of the simple composition, short length, stability to proteases, and membrane targeting, the designed peptides are attractive leads for developing novel anti-MRSA therapeutics. Our database-derived design concept can be applied to the design of peptide mimicries to combat MRSA as well.

SUBMITTER: Mishra B

PROVIDER: S-EPMC3412535 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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Ab initio design of potent anti-MRSA peptides based on database filtering technology.

Mishra Biswajit B Wang Guangshun G

Journal of the American Chemical Society 20120719 30

To meet the challenge of antibiotic resistance worldwide, a new generation of antimicrobials must be developed. This communication demonstrates ab initio design of potent peptides against methicillin-resistant Staphylococcus aureus (MRSA). Our idea is that the peptide is very likely to be active when the most probable parameters are utilized in each step of the design. We derived the most probable parameters (e.g., amino acid composition, peptide hydrophobic content, and net charge) from the ant ...[more]

PMID: 22803960

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Project description:Antimicrobial peptides (AMPs) are ubiquitous amongst living organisms and are part of the innate immune system with the ability to kill pathogens directly or indirectly by modulating the immune system. AMPs have potential as a novel therapeutic against bacteria due to their quick-acting mechanism of action that prevents bacteria from developing resistance. Additionally, there is a dire need for therapeutics with activity specifically against Gram-negative bacterial infections that are intrinsically difficult to treat, with or without acquired drug resistance. Development of new antibiotics has slowed in recent years and novel therapeutics (like AMPs) with a focus against Gram-negative bacteria are needed. We designed eight novel AMPs, termed PHNX peptides, using ab initio computational design (database filtering technology combined with the novel positional analysis on APD3 dataset of AMPs with activity against Gram-negative bacteria) and assessed their theoretical function using published machine learning algorithms, and finally, validated their activity in our laboratory. These AMPs were tested to establish their minimum inhibitory concentration (MIC) and half-maximal effective concentration (EC50) under CLSI methodology against antibiotic resistant and antibiotic susceptible Escherichia coli and Staphylococcus aureus. Laboratory-based experimental results were compared to computationally predicted activities for each of the peptides to ascertain the accuracy of the computational tools used. PHNX-1 demonstrated antibacterial activity (under high and low-salt conditions) against antibiotic resistant and susceptible strains of Gram-positive and Gram-negative bacteria and PHNX-4 to -8 demonstrated low-salt antibacterial activity only. The AMPs were then evaluated for cytotoxicity using hemolysis against human red blood cells and demonstrated some hemolysis which needs to be further evaluated. In this study, we successfully developed a design methodology to create synthetic AMPs with a narrow spectrum of activity where the PHNX AMPs demonstrated higher antibacterial activity against Gram-negative bacteria compared to Gram-positive bacteria. Thus, these peptides present novel synthetic peptides with a potential for therapeutic use. Based on our findings, we propose upfront selection of the peptide dataset for analysis, an additional step of positional analysis to add to the ab initio database filtering technology (DFT) method, and we present laboratory data on the novel, synthetically designed AMPs to validate the results of the computational approach. We aim to conduct future in vivo studies which could establish these AMPs for clinical use.

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Ab initio design of potent anti-MRSA peptides based on database filtering technology.

Publications

Ab initio design of potent anti-MRSA peptides based on database filtering technology.

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