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 <i>Staphylococcus aureus</i> (MRSA) infections. The lead compound <b>12</b> 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.