Polyamines Induce Resistance to Cationic Peptide, Aminoglycoside, and Quinolone Antibiotics in Pseudomonas aeruginosa PAO1

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Abstract
Pseudomonas aeruginosa, a gram-negative bacterium of human pathogens, is noted for its environmental versatility, enormous metabolic capacity, and resistance to antibiotics. Overexpression of the outer membrane protein OprH and increased resistance to polycationic peptide antibiotics (e.g., polymyxin B) mediated by the PhoPQ two-component system on induction of a putative lipopolysaccharide (LPS) modification operon (PA3552-PA3559) have been reported as part of the adaptive responses to magnesium limitation in P. aeruginosa. Induction of the oprH-phoPQ operon and the LPS modification operon by exogenous spermidine was revealed from GeneChip analysis during studies of polyamine metabolism and was confirmed by the lacZ fusions of affected promoters. From the results of MIC measurements, it was found that addition of spermidine or other polyamines to the growth medium increased the MIC values of multiple antibiotics, including polycationic antibiotics, aminoglycosides, quinolones, and fluorescent dyes. MIC values of these compounds in the transposon insertion mutants of oprH, phoP, phoQ, and pmrB were also determined in the presence and absence of spermidine. The results showed that the spermidine effect on cationic peptide antibiotic and quinolone resistance was diminished in the phoP mutant only. The spermidine effect on antibiotics was not influenced by magnesium concentrations, as demonstrated by MICs and oprH::lacZ fusion studies in the presence of 20 muM or 2 mM magnesium. Furthermore, in spermidine uptake mutants, MICs of cationic peptide antibiotics and fluorescent dyes, but not of aminoglycosides and quinolones, were increased by spermidine. These results suggested the presence of a complicated molecular mechanism for polyamine-mediated resistance to multiple antibiotics in P. aeruginosa.