Microbisporicin is a potent type I
lantibiotic produced by the rare actinomycete Microbispora corallina that is in preclinical trials for the treatment of
infections caused by methicillin-resistant isolates of Staphylococcus aureus (MRSA). Analysis of the gene cluster for the biosynthesis of
microbisporicin, which contains two unique post-translationally modified residues (5-chlorotryptophan and 3, 4-dihydroxyproline), has revealed an unusual regulatory mechanism that involves a pathway-specific extracytoplasmic function
sigma factor (MibX)/anti-
sigma factor (MibW) complex and an additional transcriptional regulator MibR. A model for the regulation of
microbisporicin biosynthesis derived from transcriptional, mutational and quantitative reverse transcription polymerase chain reaction analyses suggests that MibR, which contains a C-terminal
DNA-binding domain found in the LuxR family of transcriptional activators, functions as an essential master regulator to trigger
microbisporicin production while MibX and MibW induce feed-forward biosynthesis and producer immunity. Moreover, we demonstrate that initial expression of mibR, and thus
microbisporicin production, is dependent on the
ppGpp synthetase gene (relA) of M. corallina. In addition, we show that constitutive expression of either of the two positively acting regulatory genes, mibR or mibX, leads to precocious and enhanced
microbisporicin production.