New Insight into the Mechanism of Action of and Resistance to Isoniazid: Interaction of Mycobacterium tuberculosis enoyl-ACP Reductase with INH-NADP

摘要

Genetic selection for resistance to antibiotics is a time-honored and sensitive method for the identification of molecular targets for antibiotics. The currently understood mechanism of action of INH has, in fact, been largely deciphered using these methods. However, there are numerous examples where antibiotic resistance is the result of the expression of proteins that are not themselves targets. Conspicuous among these nontarget resistance determinants are enzymes that can no longer activate the prodrug, covalently modify the antibiotic or modify the target, or actively efflux the drug from the cell. Thus, resistance alone is insufficient evidence for defining molecular targets. In the particular case of INH, the activation by KatG and subsequent formation of 12 pyridine nucleotide adducts that are bisubstrate analogues complicates the situation even further. However, the data presented here demonstrate how expression of InhA, a molecular target itself, can generate high level resistance to INH.