Polyamines Increase Antibiotic Susceptibility in Pseudomonas aeruginosa

Abstract

Pseudomonas aeruginosa is an opportunistic human pathogen. Treatment is complicated by frequent acquired resistance to antipseudomonal therapies. Polyamines (cadaverine, putrescine, spermidine, and spermine) are ubiquitous polycationic compounds essential for all living organisms. In a dose-dependent manner, polyamines increased the susceptibility of P. aeruginosa to 14 ␤-lactam antibiotics, chloramphenicol, nalidixic acid, and trimethoprim as demonstrated by a reduction in MIC of up to 64-fold. This effect was partially antagonized (25 to 50%) by the presence of 10 mM of Mg 2؉ or Ca 2؉ . In contrast, the effects of the outer membrane permeabilizers, polymyxin B nonapeptide and EDTA, were completely abolished by 3 mM Mg 2؉ or Ca 2؉ . Changes on the outer membrane barrier by these compounds were assessed by activity measurements of periplasmic ␤-lactamase. The results showed that while EDTA and polymyxin B serve as outer membrane disorganizing agents as expected, exogenous spermidine and spermine did not exhibit any apparent effect on outer membrane permeability or rupture. In summary, these results strongly suggest that the increased antibiotic susceptibility by polyamines is exerted by a mechanism that differs from that of EDTA and polymyxin B. Polyamines might be potentially useful in antipseudomonal therapies by increasing the effectiveness of certain ␤-lactam antibiotics.

A PhoPQ-Regulated ABC Transporter System Exports Tetracycline in Pseudomonas aeruginosa

“…The MIC of antibiotics was determined by broth microdilution method according to the guidelines of the Clinical and Laboratory Standards Institute (47,48). Briefly, 96-well plates containing 2-fold dilution of antibiotics were prepared in Mueller-Hinton broth, and wells were inoculated with ϳ10 5 CFU/ml of overnight bacterial cultures.…”

Dissemination and Genetic Structure of Carbapenemase Encoding Genes (bla<sub>OXA-23</sub> and bla<sub>OXA-24</sub>) in <i>Acinetobacter baumannii</i> from Southern Texas

“…Two carbapenem resistant clinical isolates (A21 for OXA-23 positiveand H1 for OXA-24 positive) were confirmed as rifampicin susceptible (MIC 0.5 μg/mL) and used as donor strains for conjugative transfer of carbapenem resistance. Mating conditions for the donor and recipient strains were essentially identical as described previously [21] except for an extended-mating period (16 to 18 hours). The mating mixtures were spread on LB agar plates containing meropenem (5 μg/mL) or carbenicillin (100 μg/mL) and rifampicin (100 μg/mL).…”

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

“…However, other studies show that polyamines can sensitize E. coli, S. aureus, Salmonella and P. aeruginosa to most β-lactams effectively increasing susceptibility against these and other drugs (886,893). The reduction in MIC suggested that any possible decrease in permeability, caused by polyamine inhibition of porin transport, did not play a major role or was not enough of a factor to generate resistance against most β-lactams in those studies (886,893).…”

“…This reduction in resistance was not linked to a decrease in expression of ampC or to disruption of the outer membrane as expected of polycationic ions which are known to be outer membrane disorganizers (886). Similarly, A. baumannii clinical and lab strains were shown to be more susceptible to the β-lactams aztreonam, carbenicillin, piperacillin and ticarcillin when treated with spermine and spermidine, but only a slight to moderate effect was observed against ceftazidime or meropenem (887).…”

“…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).…”