Introducing RpsA Point Mutations Δ438A and D123A into the Chromosome of Mycobacterium tuberculosis Confirms Their Role in Causing Resistance to Pyrazinamide

Pyrazinamide (PZA) is a unique frontline drug for shortening tuberculosis (TB) treatment, but its mechanisms of action are elusive. We previously found one PZA-resistant strain that harbors an alanine deletion at position 438 (Δ438A) in RpsA, a target of PZA associated with PZA resistance, but its role in causing PZA resistance has been inconclusive. Here, we introduced the RpsA Δ438A mutation along with the D123A mutation into the Mycobacterium tuberculosis chromosome and demonstrated that these RspA mutations are indeed responsible for PZA resistance.