9.B.282. The Isoniazid-resistance (IniABC) Family
Isoniazid-induced genes, iniA, iniB, and iniC, were identified. IniB is homologous to cell wall proteins, and IniA contains a phosphopantetheine attachment site motif, suggestive of an acyl carrier protein. IniA is also induced by the antibiotic ethambutol, an agent that inhibits cell wall biosynthesis by a mechanism that is distinct from isoniazid (Alland et al. 1998; Ramaswamy et al. 2000). The operon responds to cell wall biosynthesis inhibition (Alland et al. 2000). Both IniA and IniB are essential for ethambutol resistance (Ahmad et al. 2004). Colangeli et al. 2005 showed that IniA is essential for the activity of a drug efflux system. Overexpression of iniA conferred resistance to ethidium bromide, and the deletion of iniA in M. tuberculosis resulted in increased accumulation of intracellular ethidium bromide. The pump inhibitor reserpine reversed both tolerance to isoniazid and resistance to ethidium bromide. Thus, IniA functions through an MDR-pump like mechanism, although IniA does not appear to directly transport INH from the cell. Analysis of two-dimensional crystals of the IniA protein revealed that this predicted transmembrane protein forms multimeric structures containing a central pore, providing further evidence that IniA is a pump component (Colangeli et al. 2005). Mutations in the iniA, iniB and iniC genes gave rise to isoniazid-sensitivity (Zhang et al. 2005). The operon is repressed by the Lsr2 histone-like AT-rich DNA binding protein that also represses the efpA efflux protein gene. EfpA is a drug resistance protein of the MFS (TC# 2.A.1.3.78), so the iniABC operon could be acting through this system (Colangeli et al. 2007).