The increasing pervasiveness of infections caused by multidrug-resistant bacteria (MDR) is a major global health issue that has been further exacerbated by the dearth of antibiotics developed over the past 40 years. Drug-resistant bacteria have led to significant morbidity and mortality, and ever-increasing antibiotic resistance threatens to reverse many of the medical advances enabled by antibiotics over the last 40 years. The traditional strategy for combating these superbugs involves the development of new antibiotics. Yet, only two new classes of antibiotics have been introduced to the clinic over the past two decades, and both failed to combat broad spectrum gram-negative bacteria. This situation demands alternative strategies to combat drug-resistant superbugs. Herein, these dissertation reports the development of potent antibacterials based on biomolecule-encapsulated two-dimensional inorganic materials, which combat multidrug-resistant bacteria using alternative mechanisms of strong physical interactions with bacterial cell membrane. These systems successfully eliminate all members of the ‘Superbugs’ set of pathogenic bacteria, which are known for developing antibiotic resistance, providing an alternative to the limited ‘one bug-one drug’ approach that is conventionally used. Furthermore, these systems demonstrate a multimodal antibacterial killing mechanism that induces outer membrane destabilization, unregulated ion movement across the membranes, induction of oxidative stress, and finally apoptotic-like cell death. In addition, a peptide-encapsulation of the two-dimensional material successfully eliminated biofilms and persisters at micromolar concentrations. Overall, these novel systems have great potential as next-generation antimicrobial agents for eradication of broad spectrum multidrug-resistant bacteria.