The rapid rise of multidrug-resistant (MDR) superbugs and the declining antibiotic pipeline are serious challenges to global health. Rational design of therapeutics can accelerate development of effective therapies against MDR bacteria. In this talk, I will describe multi-pronged systems, synthetic biology, and nano-biotechnology based approaches being devised in our lab to rationally engineer therapeutics that can overcome antimicrobial resistance. We have developed Synthetic biology-based approach dubbed “Controlled Hindrance of Adaptation of OrganismS” or “CHAOS” to slow the evolution of antibiotic resistance by interfering with the processes involved in adaptive resistance. To translate our findings into the clinical setting, we have engineered antisense therapeutics that can block translation or increase transcription of any desired gene in a species-specific manner for targeted inhibition. Using this approach we have built a Facile Accelerated Specific Therapeutic (FAST) platform for the accelerated therapeutics in less than a week. Finally, I will also present a nano-biotechnology based approach involving development of a unique semiconductor material based quantum dot-antibiotic (QD ABx) which, when activated by stimuli, release reactive oxygen species to eliminate a broad range of MDR bacterial clinical isolates. The CHAOS, FAST and QD Abx platforms and inter-disciplinary approaches presented in this talk offer novel methods for rationally engineering new therapeutics to combat disease challenges.