Discovery of adamantane-containing small-molecule peptidomimetics with membrane-disrupting activity for combating drug-resistant Bacteria

The rising incidence of drug-resistant bacterial infections poses a significant threat to human health and highlights the urgent need for novel antimicrobial agents. In the present study, inspired by cationic antimicrobial peptides (AMPs) we developed a series of amphiphilic small-molecule peptidomimetics by incorporating adamantane as the hydrophobic moiety and alkylamines as hydrophilic moiety into the scaffold of natural amino acids to combat drug-resistant bacteria. Among them, the optimized compound A13 exhibited broad spectrum antimicrobial activity, especially against various Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus gallinarum, while maintaining high cell compatibility. A13 rapidly killed bacteria primarily through membrane disruption, a mechanism that reduces the likelihood of resistance development. Additionally, A13 demonstrated significant anti-biofilm activity, excellent stability, and effective in vivo therapeutic efficacy in mouse models of MRSA-induced keratitis and pneumonia. Therefore, this study holds promise in providing effective antimicrobial agents or new strategies for the discovery of novel antibiotics to treat drug-resistant bacterial infections.