A Single-Nucleotide Substitution Generates a de Novo Promoter That Activates a Latent Metabolic Bypass in Escherichia...

The Escherichia coli fabH gene encodes the 3-ketoacyl-ACP synthase III that initiates fatty acid synthesis. Deletion of the fabH gene results in severely limited fatty acid synthesis and tiny cells that are unusually sensitive to antibiotics. Genetic investigations identified the yiiD gene, now called madA, that encodes a malonyl-ACP decarboxylase that suppresses the ∆fabH phenotype, but only when madA is multicopy. We selected vancomycin-resistant suppressor derivatives of a ∆fabH strain. Although such chromosomal mutations were generally rare and weak, suppressor strain s1 (a single C-T transition) restored both wild-type growth, high-level vancomycin resistance, and wild-type fatty acid synthesis by creation of a new promoter within the coding sequence of a gene upstream of madA. This provides a caveat to the extensive effort to develop FabH inhibitors as antibacterial drugs.