Novel Feleucin-K3-Derived Peptides Modified with Sulfono-γ-AA Building Blocks Targeting Pseudomonas aeruginosa and Methicillin-Resistant Staphylococcus aureus Infections

The prevalence of multidrug-resistant bacterial infections has
led to dramatically increased morbidity and mortality. Antimicrobial
peptides (AMPs) have great potential as new therapeutic agents to
reverse this dangerous trend. Herein, a series of novel AMP Feleucin-K3
analogues modified with unnatural peptidomimetic sulfono-γ-AA
building blocks were designed and synthesized. The structure–activity,
structure–toxicity, and structure–stability relationships
were investigated to discover the optimal antimicrobial candidates.
Among them, K122 exhibited potent and broad-spectrum antimicrobial
activity and high selectivity. K122 had a rapid bactericidal effect
and a low tendency to induce resistance. Surprisingly, K122 showed
excellent effectiveness against bacterial pneumonia. For biofilm and
local skin infections, K122 significantly decreased the bacterial
load and improved tissue injury at a dose of only 0.25 mg/kg, which
was 160 times lower than the concentration deemed to be safe for local
dermal applications. In summary, K122 is an outstanding candidate
for the treatment of multidrug-resistant bacteria and biofilm infections.