Leprosy remains a major public health problem due to single and multi-drug resistance. This study proposes a multi-targeted therapy by targeting MurC, MurD, MurE, and MurF enzymes of the peptidoglycan biosynthetic pathway. Conserved active site residues important for enzyme function were identified using evolutionary trace analysis. Residues G125, K126, T127, G293 (MurC) and K143, T144, T166, G168, H234, Y329 (MurE) were identified as key for drug design to overcome resistance. © 2012 Elsevier B.V. © 2013 Elsevier B.V., All rights reserved.