Characterization of the Mycobacterium tuberculosis iniBAC promoter, a promoter that responds to cell wall biosynthesis inhibition

The cell wall provides an attractive target for antibiotics against Mycobac terium tuberculosis. Agents such as isoniazid and ethambutol that work by i nhibiting cell wall biosynthesis are among the most highly effective antibi otics against this pathogen. Although considerable progress has been made i dentifying the targets for cell wall active antibiotics, little is known ab out the intracellular mechanisms that are activated as a consequence of cel l wall injury. These mechanisms are likely to have. an important role in gr owth regulation and in the induction of cell death by antibiotics. We previ ously discovered three isoniazid-induced genes (iniB, iniA, and iniC) organ ized in tandem on the M. tuberculosis genome. Here, we investigate the uniq ue features of the putative iniBAC promoter. This promoter was specifically induced by a broad range of inhibitors of cell wall biosynthesis but was n ot inducible by other conditions that are toxic to mycobacteria via other m echanisms. Induction required inhibitory concentrations of antibiotics and could be detected only in actively growing cells. Analysis of the iniBAC pr omoter sequence revealed both a regulatory element upstream and a potential repressor binding region downstream of the transcriptional start site. The induction phenotype and structure of the iniBAC promoter suggest that a co mplex intracellular response occurs when cell wall biosynthesis is inhibite d in M, tuberculosis and other mycobacteria.