Infections caused by multidrug-resistant (MDR) bacteria pose a serious global burden of mortality, causing thousands of deaths each year. The “superbug” risk is further exacerbated by chronic infections generated from antibiotic-resistant biofilms that are highly resistant to available treatments. Synthetic macromolecules such as polymers and nanoparticles have emerged as promising antimicrobials. Moreover, ability to modulate nanomaterial interaction with bacterial cellular systems plays a pivotal role in improving the efficacy of the strategy. In the initial studies on engineering nanoparticle surface chemistry, I investigated the role played by surface ligands in determining the antimicrobial activity of the nanoparticles. In further study, I determined that surface monolayer of hydrophobic ligands facilitated the nanoparticles to block bacterial efflux pumps, yielding reduction in antibiotic dosage to treat pathogenic bacteria including methicillin-resistant S. aureus (MRSA). Moreover, functionalization of nanoparticle surface with pH-responsive ligand was used to develop a general strategy to target and image bacterial biofilms for a broad-range of species. In a subsequent study, I have utilized a unique approach of integrating synthetic nanomaterials on the surface of natural super carrier-Red Blood Cells for selective delivery of nanoparticles to the site of bacterial infection for antimicrobial therapy. This strategy shows potential to combat bacterial infections without harming the ecology of human microbiome, as well as circumvent the issues associated with non-specific uptake of nanoparticles by the reticuloendothelial system. In another study, systematic investigation of antimicrobial activity of oxanorbornene-polymer derivatives generated polymer nanoparticles with unprecedented therapeutic selectivity towards MDR bacteria. Additionally, polymeric nanoparticles prevented onset of resistance development in bacteria for ~1300 generations and eradicate biofilms on infected mammalian cells, a feat unachieved by previous antimicrobial polymers. Amphiphilic polymer derivates increased the influx of antibiotics in Gram-negative bacteria and biofilms, resulting in synergistic antimicrobial therapy. Subsequently, we utilized engineered polymers to generate nanosponges through self-assembly of polymers around essential-oil based cores for topical treatment of wound biofilms. Overall, our results show strong potential as an infectious disease therapeutic while simultaneously provide a rational approach to design novel antimicrobials for sustainably combating bacterial infections.