Fluorinated multi-mechanism antimicrobial peptides for improved potency against multidrug-resistant bacterial...

Antimicrobial peptides (AMPs) are promising alternatives to antibiotics; however, their development is often hampered by poor stability, safety concerns, and uncertain resistance risk. Therefore, this study aimed to develop new AMPs with enhanced stability, safety, and low resistance potential against multidrug-resistant bacteria.

A fluorination-based modification strategy was used to develop new AMPs, and their antimicrobial activity, stability, safety, mechanism, resistance development, and in vivo efficacy and safety were evaluated.

A series of fluorinated AMPs was designed and synthesized, and Hrk8 was identified the lead candidate, which exhibited potent activity against multidrug-resistant bacteria, good stability and a favourable safety profile. Hrk8 operated via a multi-mechanism, including rapid membrane disruption, interference with intracellular processes, and species-specific transcriptional responses. In Escherichia coli, Hrk8 exposure was associated with widespread metabolic dysregulation reflecting systemic collapse of cellular homeostasis. In contrast, in methicillin-resistant Staphylococcus aureus, the transcriptional response suggested adaptive envelope remodelling and reduced virulence-associated regulatory programs. Consistent with this combined action, Hrk8 showed a low propensity to develop bacterial resistance and could limit the development of antibiotic resistance, while also exhibiting synergistic or additive antimicrobial activity and eradicating persister cells. Hrk8 achieved efficacy comparable to polymyxin B and vancomycin in mouse models of systemic infection, pneumonia and skin wound infection, but with a more favourable safety profile than polymyxin B.

Fluorination effectively generated developable AMPs, resulting in Hrk8, which exhibited potent, broad-spectrum antimicrobial activity, low resistance potential, and promising therapeutic prospects. This approach provides a practical method to combat drug-resistant infections.