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PubMedDate not supplied

Roles of porin and beta-lactamase in beta-lactam resistance of Pseudomonas aeruginosa.

Pseudomonas aeruginosa demonstrates high intrinsic resistance to most beta-lactam antibiotics. Two factors that are interrelated appear to be important in this intrinsic resistance: an inducible, chromosomally encoded type Id beta-lactamase and low outer-membrane permeability. beta-Lactamase-noninducible mutants are supersusceptible to many beta-lactam agents, whereas constitutively derepressed mutants are considerably more resistant even to so-called beta-lactamase-stable beta-lactams. For the latter mutants, by analysis of kinetics, it can be demonstrated that synergy between slow permeation across the outer membrane and slow hydrolysis of the beta-lactamase-stable beta-lactams can explain resistance. Wild-type P. aeruginosa allows outer membrane permeation of beta-lactam agents at rates 1%-8% of those measured for Escherichia coli. The majority of trans-outer-membrane channels formed by P. aeruginosa porin protein F are too small to allow passage of beta-lactam antibiotics. Nevertheless, this porin is apparently a conduit for beta-lactams, since protein F-deficient mutants have small changes in susceptibility to certain beta-lactam agents. This low outer-membrane permeability acting in synergy with beta-lactamase is probably responsible for intrinsic beta-lactam resistance in P. aeruginosa.

Anti-Bacterial Agents↗

PubMed1975

Inhibition of Cryptococcus neoformans by Pseudomonas aeruginosa.

Pseudomonas aeruginosa was found to produce a factor or factors that inhibited Cryptococcus neoformans and appeared to be extracellular because the anti-C. neoformans activity was readily demonstrable in medium after the removal and killing of Pseudomonas organisms. Production of the inhibitor material was greatest in DST Agar after prolonged incubation and was reduced in the presence of glucose. A part of the inhibitory material was found to be chromatographically distinct from pyocyanin.

Antibiosis↗

PubMed2003

The ethanol oxidation system and its regulation in Pseudomonas aeruginosa.

Pseudomonas aeruginosa ATCC 17933, when growing on ethanol, uses a pyrroloquinoline quinone (PQQ)-dependent ethanol oxidation system. The genes coding for the ethanol oxidizing enzyme, a quinoprotein ethanol dehydrogenase (QEDH), cytochrome c(550), which is an essential component of the electron transport chain and accepts the electrons from QEDH, and an NAD-dependent acetaldehyde dehydrogenase form the exaABC gene cluster. Downstream of the exaBC genes the pqqABCDE gene cluster is found, which codes for proteins essential for biosynthesis of the cofactor PQQ. Also essential for growth on ethanol are an acetyl-CoA synthetase encoded by the acsA gene and a malate:quinone oxidoreductase encoded by the mqo gene. The X-ray structure of the soluble QEDH from P. aeruginosa was solved. It is a homodimeric enzyme and, aside from differences in some loops, the folding of QEDH is very similar to the large subunit of the soluble methanol dehydrogenase of methylotrophs, and the PQQ domain of the quinohemoprotein alcohol dehydrogenase from Comamonas testosteroni and P. fluorescens. Transcription from the QEDH (exaA) promoter is regulated by a two component system: a histidine sensor kinase (ExaD), which is presumably located in the cytoplasm, and a response regulator (ExaE). The phenotypic characterization and transcription studies with six regulatory mutants indicate that seven different genes in an hierarchical organization may be involved in regulating the transcription of the ethanol oxidation system and components of acetate metabolism in P. aeruginosa.

Alcohol Oxidoreductases↗

PubMed2003

Microarray analysis of global gene expression in mucoid Pseudomonas aeruginosa.

Pseudomonas aeruginosa is the dominant pathogen causing chronic respiratory infections in cystic fibrosis (CF). After an initial phase characterized by intermittent infections, a chronic colonization is established in CF upon the conversion of P. aeruginosa to the mucoid, exopolysaccharide alginate-overproducing phenotype. The emergence of mucoid P. aeruginosa in CF is associated with respiratory decline and poor prognosis. The switch to mucoidy in most CF isolates is caused by mutations in the mucA gene encoding an anti-sigma factor. The mutations in mucA result in the activation of the alternative sigma factor AlgU, the P. aeruginosa ortholog of Escherichia coli extreme stress sigma factor sigma(E). Because of the global nature of the regulators of mucoidy, we have hypothesized that other genes, in addition to those specific for alginate production, must be induced upon conversion to mucoidy, and their production may contribute to the pathogenesis in CF. Here we applied microarray analysis to identify on the whole-genome scale those genes that are coinduced with the AlgU sigmulon upon conversion to mucoidy. Gene expression profiles of AlgU-dependent conversion to mucoidy revealed coinduction of a specific subset of known virulence determinants (the major protease elastase gene, alkaline metalloproteinase gene aprA, and the protease secretion factor genes aprE and aprF) or toxic factors (cyanide synthase) that may have implications for disease in CF. Analysis of promoter regions of the most highly induced genes (>40-fold, P < or = 10(-4)) revealed a previously unrecognized, putative AlgU promoter upstream of the osmotically inducible gene osmE. This newly identified AlgU-dependent promoter of osmE was confirmed by mapping the mRNA 5' end by primer extension. The recognition of genes induced in mucoid P. aeruginosa, other than those associated with alginate biosynthesis, reported here revealed the identity of previously unappreciated factors potentially contributing to the morbidity and mortality caused by mucoid P. aeruginosa in CF.

Alginates↗

PubMed1985

Combinations of antibiotics against Pseudomonas aeruginosa.

Pseudomonas aeruginosa continues to cause serious infections, especially bacteremias, in hospitalized and immunocompromised patients. During the past 10 years, bacteremia due to this organism has increased in frequency in many institutions, and mortality rates in patients with rapidly fatal disease remain as high as 85 percent despite antibiotic therapy. Available data do not allow firm conclusions regarding the in vivo predictive value of in vitro synergy testing for P. aeruginosa, but in vitro demonstration of synergy appears important in selecting therapy for patients with P. aeruginosa infections. Combinations of aminoglycosides (amikacin or tobramycin) with highly active antipseudomonal beta-lactam antibiotics are most likely to be associated with in vitro synergy. Experimental studies in animals models support the use of combination therapy for local and bacteremic infections. Similarly, the retrospective and prospective studies in humans suggest better survival with combinations of antimicrobials, usually including aminoglycosides and beta-lactams, in immunocompromised hosts. At present, the use of newer penicillins, piperacillin, azlocillin, or selected antipseudomonal cephalosporins, in combination with amikacin or tobramycin, appears to be the preferable antimicrobial therapy for serious P. aeruginosa infections.

Aminoglycosides↗

PubMed1976

[Kinetics of a new cephalosporinase from Pseudomonas aeruginosa].

Pseudomonas aeruginosa strain RL 39 produces an inducible cephalosporinase possessing an isoelectric point of 8,66. The kinetic constants have been measured by computerized microacidimetry. The results allow to differenciate this enzyme from the one produced by Ps. aeruginosa GN 918 (Yaginuma et al. (1973) Jap. J. Microbiol., 17, 141-149) showing a similar isoelectric point.

Amidohydrolases↗

PubMed2000

Alteration of the lipopolysaccharide structure affects the functioning of the Xcp secretory system in Pseudomonas aeruginosa.

Pseudomonas aeruginosa secretes a wide range of hydrolytic enzymes into the external medium by the Xcp secretion machinery. To better understand the role played by envelope constituents in the functioning of this type II secretory system, we have studied the influence of lipopolysaccharide (LPS) on the secretion of two extracellular enzymes, the elastase LasB and the lipase LipA. Strains with defective LPS decreased production of LasB and altered the secretion processes of both LasB and LipA without any apparent effect on the composition of the Xcp machinery. The PAO1algC strain, defective in the outer core of LPS, was leaky, as shown by the extracellular release of the periplasmic beta-lactamase. Generation of an xcpR mutation in this mutant led only to a partial accumulation of LasB within the cells, indicating that in strain PAO1algC with a functional xcpR gene, LasB was released in the extracellular medium partly by leakage and partly by secretion. The pool of LasB released into the medium by leakage was not recovered in an active form, while extracellular LasB was active when secreted via the secretory machinery. Further analysis revealed that the presence of a functional Xcp machinery is strictly required for the activation process of LasB. Our results provide evidence that the Xcp system is not fully functional when the LPS structure of P. aeruginosa is altered.

Aspartic Acid Endopeptidases↗

PubMed2002

Malate:quinone oxidoreductase is essential for growth on ethanol or acetate in Pseudomonas aeruginosa.

Pseudomonas aeruginosa ATCC 17933 growing aerobically on ethanol uses a pyrroloquinoline quinone-dependent ethanol oxidation system. A mutant with an interrupted putative mqo gene, in which malate:quinone oxidoreductase (MQO), an enzyme involved in the citric acid cycle/glyoxylate cycle, was defective, showed a severe growth defect on ethanol and was unable to grow on acetate. Glucose, lactate, succinate or malate supported growth of the mutant. However, an NAD-dependent malate dehydrogenase activity could not be detected. Complementation of the mutant by the wild-type allele of the mqo gene restored wild-type behaviour. The wild-type expressed the dye-dependent MQO and NAD(P)-dependent malic enzymes (MEs). Pyruvate carboxylase (PC) was found upon growth of the wild-type and the mutant on all substrates studied. PC activity in the wild-type was induced on glucose and lactate and was always higher on all substrates in the mqo mutant. In P. aeruginosa ATCC 17933, an active MQO is required for growth on ethanol or acetate, while with glucose, lactate, succinate or malate an apparent bypass route operates, with MEs using malate for generating pyruvate, which is carboxylated to oxaloacetate by PC. To the authors' knowledge, this is the first time that a specific mutant MQO phenotype has been observed, caused by the inactivation of a gene encoding MQO activity. mqo of P. aeruginosa ATCC 17933 corresponds to mqoB (PA4640) of the P. aeruginosa PAO1 genome project.

Acetates↗

PubMed1992

Cloning of the outer membrane high-affinity Fe(III)-pyochelin receptor of Pseudomonas aeruginosa.

Pseudomonas aeruginosa produces the phenolic siderophore pyochelin under iron-limiting conditions. In this study, an Fe(III)-pyochelin transport-negative (Fpt-) strain, IA613, was isolated and characterized. 55Fe(III)-pyochelin transport assays determined that no Fe(III)-pyochelin associated with the Fpt- IA613 cells while a significant amount associated with KCN-poisoned Fpt+ cells. A P. aeruginosa genomic library was constructed in the IncP cosmid pLAFR1. The genomic library was mobilized into IA613, and a recombinant cosmid, pCC41, which complemented the Fpt- phenotype of IA613, was isolated. pCC41 contained a 28-kb insert of P. aeruginosa DNA, and the Fpt(-)-complementing region was localized to a 3.6-kb BamHI-EcoRI fragment by deletion and subcloning of the insert. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis of IA613 revealed that it lacked a 75-kDa outer membrane protein present in Fpt+ strains. IA613 strains bearing plasmid pRML303, which carries the 3.6-kb BamHI-EcoRI fragment of pCC41, expressed the 75-kDa outer membrane protein and demonstrated a 55Fe(III)-pyochelin transport phenotype identical to that of a wild-type Fpt+ strain. Minicell analysis demonstrated that the 3.6-kb BamHI-EcoRI fragment of pCC41 encoded a protein of approximately 75 kDa. The results presented here and in a previous report (D. E. Heinrichs, L. Young, and K. Poole, Infect. Immun. 59:3680-3684, 1991) lead to the conclusion that the 75-kDa outer membrane protein is the high-affinity receptor for Fe(III)-pyochelin in P. aeruginosa.

Bacterial Outer Membrane Proteins↗

PubMed2005

Epidemiological analysis of carbapenem-sensitive and -resistant Pseudomonas aeruginosa.

Pseudomonas aeruginosa with decreased levels of meropenem susceptibility were identified in the Royal Infirmary Edinburgh in 2002. Within the affected group of patients, none had meropenem-resistant P. aeruginosa when they arrived in the intensive care unit (ICU). Seven isolates from the ICU were collected five months after the decreased susceptibility to meropenem was identified. In order to investigate if resistance was a problem in P. aeruginosa throughout Edinburgh, both in hospital- and community-acquired isolates, a prospective study was performed. The susceptibilities of 104 P. aeruginosa to imipenem, meropenem, ceftazidime, piperacillin/tazobactam and ciprofloxacin were investigated. Meropenem had the highest activity against these isolates and the lowest MIC(90) (2 mg/L), followed by imipenem (4 mg/L), ciprofloxacin (8 mg/L), piperacillin/tazobactam (16 mg/L) and ceftazidime (32 mg/L). These isolates were also analysed genotypically by pulsed-field gel electrophoresis. Five of the seven ICU isolates were identified, one isolate was 98% similar and the other was 85% similar to the ICU isolates. One isolate from the prospective study had approximately 90% genotype similarity to the six ICU isolates with >/=98% similarity. There was no clonality within the strains from the prospective study and clusters with >90% similarity comprised at five or less isolates. Isolates with the same resistance patterns did not necessarily have the same genotypic profile. Strains isolated from different patients on the same day were also not necessarily related. The conclusions of this study were that while the seven ICU isolates were clonal or highly related, they were not widespread throughout Edinburgh and the P. aeruginosa within Edinburgh were highly varied.

Carbapenems↗

PubMed2006

[Quorum sensing: a new clinical target for Pseudomonas aeruginosa?].

Pseudomonas aeruginosa is an opportunistic bacteria causing a wide variety of infections. The bacterial virulence depends on a large panel of cell-associated and extracellular factors. Quorum sensing (QS) allows cell-to-cell communication: sensing the environment, this system coordinates the expression of various genes within the bacterial population. QS is based on an interaction between a small diffusible molecule, an acylhomoserine lactone (AHL), and a transcriptionnal activator. Two QS systems, the las and rhl systems, have been identified in P. aeruginosa. The las system associates the transcriptionnal activator protein LasR and LasI responsible for the synthesis of a specific AHL: C12-HSL. This system was shown to activate the expression of a large number of virulence factors. Similarly, the rhl system associates the transcriptionnal activator protein RhlR with RhlI, which is responsible for the synthesis of another AHL: C4-HSL. Synthesis and secretion of a number of virulence factors are controlled by QS. Utilization of different animals models showed the crucial role of QS in the pathogenesis of P. aeruginosa infections. The discovery of QS has given a new opportunity to treat bacterial infection by another means than growth inhibition. New drugs inhibiting QS were recently discovered: furanone compounds can repress a large number of QS-regulated genes, including numerous P. aeruginosa virulence factor genes. Furanone administration to mice infected with P. aeruginosa significantly reduced lung bacterial load compared with the control group.

Cell Communication↗

PubMed1996

Interactions between glycoconjugates from human respiratory airways and Pseudomonas aeruginosa.

Pseudomonas aeruginosa binds to different glycoconjugates in vitro. As six other bacteria, it binds to several glycolipids, mainly asialo GM1 and asialo GM2. Asialo GM1 has been reported to exist at the surface of cystic fibrosis cells. The binding of P. aeruginosa to asialo GM1 involves the pili, especially the C-terminal part of pilin that recognizes the GaINAc(beta 1,4) Gal sequence of asialo GM1.P. aeruginosa may also bind to sialylated membrane-bound glycoproteins. Human salivary and respiratory mucins are also recognized by P. aeruginosa. Mucins represent the main components of mucus. The peptide part (apomucin) of this broad family of secreted glycoproteins is encoded by several mucin genes. The apomucins are covered by a large number of carbohydrate chains that can be remarkably different and represent a mosaic of sites for attachment of microorganisms. The binding of P. aeruginosa to mucins involves outer membrane proteins and mucin carbohydrate chains that are structurally different from the carbohydrate recognized by pillin. Airway and salivary mucins secreted by patients suffering from cystic fibrosis (CF) show alterations in their carbohydrate moiety. The increased sulfation of airway mucins seems to correspond to a primary defect. Other abnormalities such as increased sialylation or fucosylation have also been detected. The binding of P. aeruginosa to airway or salivary mucins is increased in CF. However, the precise link between the carbohydrate alterations and the increased binding of P. aeruginosa to CF mucins remains to be elucidated.

Animals↗

PubMed2006

Accumulation of copper and silver onto cell body and its effect on the inactivation of Pseudomonas aeruginosa.

Pseudomonas aeruginosa, a gram-negative rod bacterium, is a causative agent of waterborne pneumonia and presents high tolerance against conventional disinfectants. The inorganic biocidal reagents, copper and silver, were applied to inactivate P. aeruginosa inoculated in a synthetic drinking water (SDW). Additionally, the relationship of the specific amount of accumulated copper and silver reagents (Cs) on P. aeruginosa with inactivation profile was elucidated in this study. Flow cytometry (FCM) following staining with SYTO 9 and PI was used for detection of bacterial viability and density. Individual copper and silver reagents, and their combination, exhibited excellent biocidal abilities even at the concentration of 0.05 mgCu/L and 0.005 mgAg/L. The critical amounts of accumulated disinfectant (Cs) were calculated at 2.82 x 10(-7) microgCu/cells and 5.13 x 10(-8) microgAg/cells; at an incubation of 70 h. Consequently, the role of disinfectant on the inactivation of P. aeruginosa and the assessment of biocidal ability of copper, silver, and their combination were successfully explained by evaluating the terms Cs and Cc.

Copper↗

PubMed2004

Modeling the effect of acylated homoserine lactone antagonists in Pseudomonas aeruginosa.

Pseudomonas aeruginosa is a gram-negative bacterium that causes serious illnesses, particularly in immunocompromised individuals, often with a fatal outcome. The finding that the acylated homoserine lactone quorum sensing (QS) system controls the production of virulence factors in P. aeruginosa makes this system a possible target for antimicrobial therapy. It has been suggested that an N-(3-oxododecanoyl)-homoserine lactone (3O-C12-HSL) antagonist, a QS blocker (QSB), would interfere efficiently with the quorum sensing system in P. aeruginosa and thus reduce the virulence of this pathogen. In this work, a mathematical model of the QS system in P. aeruginosa has been developed. The model was used to virtually add 3O-C12-HSL antagonists that differed in their affinity for the receptor protein and for their ability to mediate degradation of the receptor. The model suggests that very small differences in these parameters for different 3O-C12-HSL antagonists can greatly affect the success of QSB based inhibition of the QS system in P. aeruginosa. Most importantly, it is proposed that the ability of the 3O-C12-HSL antagonist to mediate degradation of LasR is the core parameter for successful QSB based inhibition of the QS system in P. aeruginosa. Finally, this study demonstrates that QSBs can shift the system to a low steady state, corresponding to an uninduced state and thus, suggests that the use of 3O-C12-HSL antagonists may constitute a promising therapeutic approach against P. aeruginosa involved infections.

4-Butyrolactone↗

PubMed2001

Oxacillinase-mediated resistance to cefepime and susceptibility to ceftazidime in Pseudomonas aeruginosa.

Pseudomonas aeruginosa clinical isolate SOF-1 was resistant to cefepime and susceptible to ceftazidime. This resistance phenotype was explained by the expression of OXA-31, which shared 98% amino acid identity with a class D beta-lactamase, OXA-1. The oxa-31 gene was located on a ca. 300-kb nonconjugative plasmid and on a class 1 integron. No additional efflux mechanism for cefepime was detected in P. aeruginosa SOF-1. Resistance to cefepime and susceptibility to ceftazidime in P. aeruginosa were conferred by OXA-1 as well.

Cefepime↗

PubMed2000

RpmA is required for nonopsonic phagocytosis of Pseudomonas aeruginosa.

Pseudomonas aeruginosa causes severe respiratory tract infections in patients with cystic fibrosis (CF). We have been examining nonopsonic phagocytosis of P. aeruginosa by macrophages. To study the P. aeruginosa-macrophage interaction at the molecular level, we have constructed a transposon Tn5G bank in a clinical isolate of P. aeruginosa (strain 4020) and identified mutants resistant to nonopsonic phagocytosis. Phagocytosis-resistant mutants were enriched by passaging the transposon bank over 18 macrophage monolayers. Of 900 individual mutants isolated from this enriched pool in a nonopsonic phagocytosis assay, we identified 85 putative mutants that were resistant to phagocytosis. In this study, we have characterized one of these transposon mutants, P. aeruginosa 4020 H27A, which was poorly ingested. H27A possessed a Tn5G insertion in a gene encoding a protein with homology to the MotA proteins of several species of bacteria. We have called this gene rpmA for required for phagocytosis by macrophages. RpmA is one of two MotA paralogs in P. aeruginosa. This rpmA::Tn5G mutant was motile both on agar plates and in visual examination of wet mounts. The phagocytosis defect was partially complemented by providing the rpmA gene in trans and fully complemented when both rpmA and rpmB were provided. A rpmA null mutant was ingested by macrophages similar to the H27A transposon mutant. These data suggest that the rpmA and rpmB gene products are required for the efficient ingestion of P. aeruginosa by macrophages.

Bacterial Proteins↗

PubMed2003

CzcR-CzcS, a two-component system involved in heavy metal and carbapenem resistance in Pseudomonas aeruginosa.

Pseudomonas aeruginosa is an environmental bacterium involved in mineralization of organic matter. It is also an opportunistic pathogen able to cause serious infections in immunocompromised hosts. As such, it is exposed to xenobiotics including solvents, heavy metals, and antimicrobials. We studied the response of P. aeruginosa upon exposure to heavy metals or antibiotics to investigate whether common regulatory mechanisms govern resistance to both types of compounds. We showed that sublethal zinc concentrations induced resistance to zinc, cadmium, and cobalt, while lethal zinc concentrations selected mutants constitutively resistant to these heavy metals. Both zinc-induced and stable zinc-resistant strains were also resistant to the carbapenem antibiotic imipenem. On the other hand, only 20% of clones selected on imipenem were also resistant to zinc. Heavy metal resistance in the mutants could be correlated by quantitative real time PCR with increased expression of the heavy metal efflux pump CzcCBA and its cognate two-component regulator genes czcR-czcS. Western blot analysis revealed reduced expression of the basic amino acid and carbapenem-specific OprD porin in all imipenem-resistant mutants. Sequencing of the czcR-czcS DNA region in eight independent zinc- and imipenem-resistant mutants revealed the presence of the same V194L mutation in the CzcS sensor protein. Overexpression in a susceptible wild type strain of the mutated CzsS protein, but not of the wild type form, resulted in decreased oprD and increased czcC expression. We further show that zinc is released from latex urinary catheters into urine in amounts sufficient to induce carbapenem resistance in P. aeruginosa, possibly compromising treatment of urinary tract infections by this class of antibiotics.

Carbapenems↗

PubMed1969

Influence of carbon or nitrogen starvation on amino acid transport in Pseudomonas aeruginosa.

Pseudomonas aeruginosa was shown to utilize the majority of commonly occurring amino acids for growth as either the sole carbon or the sole nitrogen source. During carbon or nitrogen deprivation, the rates of transport of most of the amino acids remained unchanged; however, the transport rates for glutamate, alanine, and glycine increased under these conditions and the transport rates for leucine and valine decreased. Normal transport rates for these amino acids were resumed immediately upon the addition of the required nutrient. In the absence of an external source of carbon or of nitrogen, pool amino acids underwent rapid degradation. (14)C-Amino acid pulse experiments indicated that the constitutive amino acid catabolic enzymes, normally present in the organism during growth with glucose as the carbon source, were responsible for rapid pool losses. Nutrient starvation in the presence of chloramphenicol did not prevent amino acid catabolism. This enzymic activity is interpreted as providing P. aeruginosa with a selective advantage for survival during conditions of carbon or nitrogen starvation.

Alanine↗