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.