There is an urgent need to develop novel antibiotics due to the rise of multidrug-resistant (MDR)-bacteria globally. Transition state (TS) mimicking enzyme inhibitors have been shown to exhibit extremely high potency, but the knowledge of the TS structure is not easily accessible via experimental techniques. In this project, we will utilize the power of quantum mechanics/molecular mechanics (QM/MM) calculations to study the TS structures of a recently identified and validated enzyme target from Mycobacterium tuberculosis. Calculation results will be used to guide rational design of highly potent inhibitors that mimic the characteristics of TS. The designed compounds will be synthesized and further tested in vitro and in vivo against MDR-bacteria. The computational technique developed in this project can be easily applied to other enzyme targets thus will reduce the time and cost in the drug design process and the high potency of these compounds will boost treatment efficiency.