Tuberculosis (TB) remains the most deadly disease into the 21st century, causing more than two million deaths each year. Mycobacterium tuberculosis (Mtb), the causative agent of TB has infected one third of the world population. Treatment of TB takes at least six months and multiple chemotherapies. Multi-drug resistant (MDR) and extensively drug resistant (XDR) TB cases and HIV coinfection are making the situation even worse. New generation of TB drugs are urgently needed. Using target and cell based screen methods, we identified a series of potent inhibitors that can either directly or synergize with current TB drugs to effectively kill Mtb.