Oligopyridinium peptidomimetics with dual bacterial membrane and DNA targeting as resistance-resistant antibacterials

Area of Science:

• Medicinal Chemistry
• Antimicrobial Drug Discovery
• Molecular Biology

Background:

• Multidrug-resistant (MDR) bacterial infections pose a significant global health threat, driving the need for novel antibiotics.
• Antimicrobial peptidomimetics (AMPMs) show promise but face challenges in target selectivity and toxicity.
• Oligopyridinium compounds offer a potential scaffold for developing selective antimicrobial agents.

Purpose of the Study:

• To design and synthesize novel amidated oligopyridinium peptidomimetics.
• To evaluate the antibacterial activity and biosafety of these compounds.
• To elucidate the mechanism of action of the lead compound against MDR bacteria.

Main Methods:

• Synthesis of amidated oligopyridinium derivatives.
• Determination of minimum inhibitory concentrations (MICs) against a panel of bacteria.
• Cellular assays to assess membrane interaction, depolarization, and DNA binding.
• Reactive oxygen species (ROS) generation and metabolic activity assays.
• In vitro and in vivo efficacy studies in infection models (sheep blood, mammalian cells, Galleria mellonella, murine MRSA model).
• Toxicity assessments in various model organisms.

Main Results:

• A lead compound, 1c, demonstrated potent broad-spectrum antibacterial activity (MIC ≤2 μg/mL).
• Compound 1c selectively targets bacterial membranes (phosphatidylglycerol, lipopolysaccharide) and DNA, leading to membrane depolarization, perforation, ROS accumulation, and metabolic suppression.
• 1c eradicated dormant and persistent bacteria rapidly (within 2 h) and showed efficacy in complex biological matrices.
• Excellent biosafety profile with no observed toxicity in G. mellonella, zebrafish, or mice at 20 mg/kg.
• In vivo studies showed significant bacterial load reduction, with 55% survival in G. mellonella and 75% survival in a murine MRSA infection model.

Conclusions:

• Novel amidated oligopyridinium peptidomimetics exhibit potent dual-targeting antimicrobial properties.
• The lead compound 1c demonstrates broad-spectrum efficacy, rapid action, and favorable safety profiles.
• These compounds represent a promising new strategy for combating challenging multidrug-resistant bacterial infections.