Modular Design of Membrane-Active Antibiotics: From Macromolecular Antimicrobials to Small Scorpionlike Peptidomimetics

Infections caused by multidrug-resistant
bacteria have emerged
in recent decades, leading to escalating interest in host defense
peptides (HDPs) to reverse this dangerous trend. Inspired by the modular
design in bioengineering, herein we report a new class of small amphiphilic
scorpionlike peptidomimetics based on this strategy. These HDP mimics
show potent antimicrobial activity against both Gram-positive and
Gram-negative bacteria without drug resistance but with a high therapeutic
index. The membrane-compromising action mode was suggested to be their
potential bactericidal mechanism. Pharmacodynamic experiments were
conducted using a murine abscess model of methicillin-resistant Staphylococcus aureus (MRSA) infections. The lead
compound 12 showed impressive in vivo therapeutic efficacy
with ∼99.998% (4.7log) reduction in skin MRSA burden, a significantly
higher bactericidal efficiency than ciprofloxacin, and good biocompatibility.
These results highlight the potential of these HDP mimics as novel
antibiotic therapeutics.