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

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 M 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.

Growth-related changes in intracellular spermidine and its effect on efflux pump expression and quorum sensing in Burkholderia pseudomallei

“…Exogenous spermidine added to culture medium increases the resistance of Pseudomonas aeruginosa to aminoglycosides and quinolones, although no known efflux system was found to be significantly upregulated using DNA microarray analysis (Kwon & Lu, 2006). In this study, we tracked the changes in intracellular levels of spermidine and N-acetylspermidine during growth of B. pseudomallei KHW and describe the effect of such changes on the expression of the BpeAB-OprB pump, which is involved in the efflux of mostly N-acetylspermidine.…”

Polyamines Can Increase Resistance ofNeisseria gonorrhoeaeto Mediators of the Innate Human Host Defense

“…Additionally, polyamines can modify the response of microbes to antibiotics, depending on their chemical characteristics, the bacterial target, or the antimicrobial agent under investigation (7,11,21); however, specific molecular mechanisms to explain how polyamines function in this capacity remain to be determined. Since previous studies with Escherichia coli and Pseudomonas aeruginosa showed that polyamines can bind to bacterial surfaces and influence the antimicrobial action of different antibiotics (13,34), we hypothesized that similar relationships may hold for N. gonorrhoeae and host-derived antimicrobials. We now report that incubation of gonococci with sublethal levels of polyamines (e.g., spermine) reduces their susceptibility to the killing action of two structurally diverse CAMPs (PMB and LL-37) and to complement-mediated killing by NHS.…”

Characterization of the poxAB Operon Encoding a Class D Carbapenemase in Pseudomonas aeruginosa,

“…Although polyamines have not been shown to induce expression of efflux pumps, spermidine did provide resistance against cationic peptides and quinolones by inducing expression of oprH-phoPQ and the LPS modification operon (885). It is likely we don't yet know all the current targets of polyamines.…”

“…Previous work showed that polyamines decreased expression of T3SS secretions and virulence genes in PA01 (884). Polyamines were also shown to increase resistance in P. aeruginosa against aminoglycosides, with resistance against quinolones and cationic peptides being mediated by the expression of the oprH-phoPQ operon (885). In contrast, polyamines significantly increased susceptibility of P. aeruginosa against a number of β-lactams including the penicillins ampicillin, carbenicillin, piperacillin and ticarcillin, and the third generations cephalosporins ceftazidime, cefoperazone and ceftriaxone (886).…”