Development of antimicrobial peptide therapeutics for multidrug-resistant systemic bacterial infection

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Current difficulties in discovering and developing novel antibiotics is becoming a major health care crisis. This situation is even more challenging with the emergence of antimicrobial resistance. The underlying hypothesis of the proposed project is that the design of α-helical peptides in silico offers excellent possibilities for identifying novel antimicrobial compounds with respect to time efficiency and cost reduction. The long-term goal of this proposal is to utilize structure-guided principles to design novel antimicrobial peptides (AMPs) in silico that will be effective against systemic bacterial infection caused by both Gram-negative bacteria and Gram-positive bacteria. We aim to engineer short α-helical AMPs with suitable potency, selectivity, stability, and appropriate PK/PD properties. We will test our central hypothesis with three specific aims: Aim 1) In silico design of bacteria-specific AMPs that includes manual design based on a classic 3.613 α-helix core (Pauling–Corey–Branson α-helix) containing 12 amino acid residues with varying charge and hydrophobicity balance followed by molecular dynamics modeling and structure predictions using AlphaFold2. Aim 2) Determine the activity, toxicity, stability, and mechanism of action of designed peptides. Aim 3) In vivo efficacy evaluation of peptides in a Galleria mellonella wax moth model and subsequently in a systemic mouse infection model. In addition, we will also evaluate nanoparticle formulations of selected, designed AMPs for potential future in vivo use in mice using a poly(lactic-co-glycolic acid) (PLGA) and/or chitosan nanocarrier. Upon completion of the proposed objectives, novel candidate AMPs will be identified that will help mitigate the current antimicrobial crisis.