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Development of resistance to the antipseudomonal penicillins and cephalosporins mediated by hyperproduction of the chromosomal cephalosporinase AmpC is a major threat to the successful treatment ofPseudomonas aeruginosa infections. AlthoughampD inactivation has been previously found to lead to a partially derepressed phenotype characterized by increased AmpC production but retaining further inducibility, the regulation ofampC inP. aeruginosa is far from well understood. We demonstrate thatampC expression is coordinately repressed by three AmpD homologues, including the previously described protein AmpD plus two additional proteins, designated AmpDh2 and AmpDh3. The three AmpD homologues are responsible for a stepwiseampC upregulation mechanism ultimately leading to constitutive hyperexpression of the chromosomal cephalosporinase and high-level antipseudomonal β-lactam resistance, as shown by analysis of the three singleampD mutants, the three doubleampD mutants, and the tripleampD mutant. This is achieved by a three-step escalating mechanism rendering four relevant expression states: basal-level inducible expression (wild type), moderate-level hyperinducible expression with increased antipseudomonal β-lactam resistance (ampD mutant), high-level hyperinducible expression with high-level β-lactam resistance (ampD ampDh3 double mutant), and very high-level (more than 1,000-fold compared to the wild type) derepressed expression (triple mutant). Although one-step inducible-derepressed expression models are frequent in natural resistance mechanisms, this is the first characterized example in which expression of a resistance gene can be sequentially amplified through multiple steps of derepression.

antimicrobial agents and chemotherapy

Stepwise Upregulation of the<i>Pseudomonas aeruginosa</i>Chromosomal Cephalosporinase Conferring High-Level β-Lactam Resistance Involves Three AmpD Homologues

Stepwise Upregulation of thePseudomonas aeruginosaChromosomal Cephalosporinase Conferring High-Level β-Lactam Resistance Involves Three AmpD Homologues