Isoamphipathic antibacterial molecules regulating activity and toxicity through positional isomerism

Area of Science:

• Medicinal Chemistry
• Antimicrobial Drug Discovery
• Molecular Design

Background:

• Peptidomimetic antimicrobials rely on amphiphilic balance for selective bacterial cell interaction.
• Existing optimization of hydrophobicity and cationic charge is insufficient to prevent mammalian cell toxicity.
• Positional isomerism has not been fully explored as a design factor for antimicrobial selectivity.

Purpose of the Study:

• To design and synthesize novel isoamphipathic antibacterial molecules (IAMs) utilizing positional isomerism.
• To evaluate the antibacterial activity and mammalian cell toxicity of these IAMs.
• To establish the role of positional isomerism in achieving selective and potent antibacterial agents.

Main Methods:

• Synthesis of isoamphipathic antibacterial molecules (IAMs) with varying positional isomerism (ortho, meta, para).
• Determination of minimum inhibitory concentrations (MIC) and half-maximal cytotoxic concentrations (HC50) for IAMs.
• Co-culture studies and membrane dynamics investigations.
• Molecular dynamics simulations to elucidate the mechanism of action.
• In vivo efficacy testing in a murine wound infection model.

Main Results:

• IAMs displayed good to moderate antibacterial activity against Gram-positive and Gram-negative bacteria.
• Positional isomerism significantly influenced antibacterial activity and toxicity; the ortho-isomer (IAM-1) showed the best selectivity.
• IAM-1 exhibited potent activity against dormant bacteria and mature biofilms.
• IAM-1 demonstrated moderate in vivo efficacy against MRSA wound infection with no detectable dermal toxicity.

Conclusions:

• Positional isomerism is a crucial factor in designing selective and potent peptidomimetic antimicrobials.
• The ortho-isomer, IAM-1, represents a promising lead compound with enhanced bacterial selectivity and reduced mammalian cell toxicity.
• IAM-1 shows potential for combating challenging bacterial infections, including those involving biofilms and dormant cells.