Therapeutic potential and safety challenges of antimicrobial peptides and peptidomimetics against ESKAPEE pathogens:...

Antimicrobial peptides and peptidomimetics have emerged as promising alternatives to traditional antibiotics for MDR bacterial infections. Their advancement, however, is often limited by toxicity and poor pharmacokinetics. In this review, we apply a rigorous quantitative framework to evaluate the therapeutic balance of potency and safety for these agents, offering new perspectives that extend beyond previous descriptive analyses.

We systematically searched key biomedical databases (January 2000 to May 2025) for studies reporting antimicrobial potency, cytotoxicity, selectivity index, stability and in vivo efficacy. Bias was assessed using an adapted laboratory animal experimentation quality tool. Data were synthesized using a pooled geometric mean approach to compare therapeutic windows across compound.

Of 136 peptides from 47 studies, natural antimicrobial peptides were most potent in vitro against Gram-negative bacteria but frequently caused significant host toxicity. Limited cytotoxicity data prevented robust selectivity analysis for these natural compounds. Peptidomimetics generally provided a wider safety margin than synthetic peptides, though toxicity was context dependent. Major translational barriers, including protein binding and cation effects, diminished in vivo efficacy. Notably, some rationally designed compounds achieved therapeutic benefit in animal models without acute toxicity, unlike traditional agents such as polymyxin B.

Advancing antimicrobial peptides and peptidomimetics into clinical use will require overcoming the fundamental trade-off between potency and safety. Natural compounds remain restricted by toxicity, while synthetic agents and peptidomimetics promise better safety but face pharmacokinetic challenges. Future research should prioritize innovative delivery approaches to enhance efficacy and reduce toxicity, enabling these novel therapies to address MDR infections.