The mycobacterial ClpC1 is an essential and conserved protein that associates with ClpP peptidase to degrade protein substrates and maintain cellular homeostasis in M. tb. The discovery of natural product inhibitors of ClpC1 with high selectivity and potency against M. tb has established ClpC1 as a promising novel drug target. A series of potent analogues of natural products has been developed with superior pharmacokinetic properties and demonstrated efficacy in vivo. Lead optimization efforts are ongoing.