Pursuing the search for a new class of structurally simple mimics of antimicrobial peptides, we optimized a short, cheap and high-yielding synthesis of mono-charged amphiphilic α-hydrazido acid derivatives. The most active derivatives furnished MICs that are among the best values reported in literature for synthetic amphiphilic membranolytic compounds. They exhibited a broad-spectrum in vitro activity against a variety of Gram-positive and Gram-negative bacteria, including two multidrug-resistant strains. In spite of the minimal cationic charge, the best compounds demonstrated to be selective toward bacterial cell membranes over mammalian cell membranes. The relationship between either the antibacterial or the hemolytic activity and the overall lipophilicity furnished an easy way to individuate the best dimensional range for the hydrophobic portions. The importance of a non-disrupted amphiphilicity was also demonstrated. Considering the bioactivity profile and the ease of synthesis, these chemically and proteolitically stable hydrochlorides are suitable for development of a new class of wide-spectrum antibiotics.