The Periplasmic Murein Peptide-Binding Protein MppA Is a Negative Regulator of Multiple Antibiotic Resistance in Escherichia coli

Abstract

ABSTRACTMppA is a periplasmic binding protein inEscherichia coliessential for uptake of the cell wall murein tripeptidel-alanyl-γ-d-glutamyl-meso-diaminopimelate. We have found serendipitously thatE. coliK-12 strains carrying a null mutation inmppAexhibit increased resistance to a wide spectrum of antibiotics and to cyclohexane. Normal sensitivity of themppAmutant to these agents is restored bymppAexpressed from a plasmid. As is observed in the multiple antibiotic resistance phenotype inE. colicells, themppAnull mutant overproduces the transcriptional activator, MarA, resulting in expression of the membrane-bound AcrAB proteins that function as a drug efflux pump. Reduced production of OmpF similar to that observed in the multiple antibiotic resistance phenotype is also seen in themppAmutant. These and other data reported herein indicate that MppA functions upstream of MarA in a signal transduction pathway to negatively regulate the expression ofmarAand hence of the MarA-driven multiple antibiotic resistance. Overproduction of cytoplasmic GadA and GadB and of several unidentified cytoplasmic membrane proteins as well as reduction in the amount of the outer membrane protein, OmpP, in themppAnull mutant indicate that MppA regulates a number of genes in addition to those already known to be controlled by MarA.