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At least 307 records · Page 17Linked to original sources
PubMed2006

Growth inhibition mediated by excess negative supercoiling: the interplay between transcription elongation, R-loop formation and DNA topology.

It has been known for a long time that supercoiling can affect gene expression at the level of promoter activity. Moreover, the results of a genome-wide analysis have recently led to the proposal that supercoiling could play a role in the regulation of gene expression at this level by acting as a second messenger, relaying environmental signals to regulatory networks. Although evidence is lacking for a regulatory role of supercoiling following transcription initiation, recent results from both yeast and bacteria suggest that the effect of supercoiling on gene expression can be considerably more dramatic after this initiation step. Transcription-induced supercoiling and its associated R-loops seem to be involved in this effect. In this context, one major function of topoisomerases would be to prevent the generation of excess negative supercoiling by transcription elongation, to inhibit R-loop formation and allow gene expression. This function would be especially evident when substantial and rapid gene expression is required for stress resistance, and it may explain, at least in part, why topoisomerase I synthesis is directed from stress-induced promoters in Escherichia coli. Growth inhibition mediated by excess negative supercoiling might be related to this interplay between transcription elongation and supercoiling.

DNA, Bacterial↗
PubMed2002

Interplay of topology and chemical stability on the electronic transport of molecular junctions.

The coherent electronic transport through molecular junctions is theoretically modeled. The interplay of geometry, topology, and chemistry is explored within the Landauer picture of elastic scattering and various methods of quantum description of the composite system. The emphasis is on obtaining guiding principles for device optimization. Outstanding problems and future directions are outlined.

Electric Conductivity↗
PubMed1988

Tissue and mechanical valves: mutually advantageous interplay.

This report is concerned with the dynamic interplay between glutaraldehyde preserved tissue valves (bioprostheses) and mechanical valves. These two classes of valve replacement devices are not competitive, but provide some nonoverlapping characteristic advantages and disadvantages. By proper selection, it may be possible to tailor the kind of device used for a particular patient, thus improving the overall results of bioprosthetic and mechanical valve replacement. Careful selection of patients according to age and the safety of anticoagulation should achieve a series of patients with mechanical and bioprosthetic valves that would be superior to a series in which all patients received a single device. Thus, these devices should be viewed as complimentary rather than competitive since the value of properly matching a prosthesis to the patient will be reflected in improved overall results with each class of prosthesis.

Age Factors↗
PubMed2025

Barley resistance and susceptibility to fungal cell entry involve the interplay of ROP signaling with phosphatidylinositol-monophosphates.

Rho-of-plant small GTPases (ROPs) are regulators of plant polar growth and of plant-pathogen interactions. The barley ROP, RACB, is involved in susceptibility toward infection by the barley powdery mildew fungus Blumeria hordei (Bh) but little is known about the cellular pathways that connect RACB signaling to disease susceptibility. Here we identify novel RACB interaction partners of plant or fungal origin by untargeted co-immunoprecipitation of constitutively active (CA) RACB tagged by green fluorescent protein from Bh-infected barley epidermal layers and subsequent analysis by liquid chromatography-coupled mass spectrometry. Three of the immunoprecipitated proteins, a plant phosphoinositide phosphatase, a plant phosphoinositide phospholipase, and a putative Bh-effector protein, are involved in the barley-Bh-pathosystem and support disease resistance or susceptibility, respectively. RACB and its plant interactors bind to overlapping anionic phospholipid species in vitro, and in the case of RACB, this lipid interaction is mediated by its carboxy-terminal polybasic region (PBR). Fluorescent markers for anionic phospholipids show altered subcellular distribution in barley cells during Bh attack and under expression of a RACB-binding fungal effector. Phosphatidylinositol 4-phosphate, phosphatidylinositol 3,5-bisphosphate, and phosphatidylserine show a distinct enrichment at the haustorial neck region, suggesting a connection to subcellular targeting of RACB at this site. The interplay of ROPs with anionic phospholipids and phospholipid-metabolizing enzymes may thus enable the subcellular enrichment of components pivotal for success or failure of fungal penetration.

Hordeum↗
PubMed1981

The interplay between hydrogen ions, bicarbonate ions and osmolality in the anterior duodenum modulating gastric function in the conscious calf.

1. Gastric emptying, gastric acid and pepsinogen secretion were assessed simultaneously in the conscious calf using the test meal and duodenal perfusion technique (Bell & Mostaghni, 1975).2. Duodenal infusion of NaCl at a constant osmolality of 300 m-osmole/kg, but with pH ranging from 2.0 to 12.0, did not alter the high level of gastric emptying and secretion already reported for isotonic NaCl or NaHCO(3) alone (Bell & Mostaghni, 1975; Bell & Webber, 1979). Gastric function, therefore, is either unaffected by gastric chyme at pH 2.0-12.0 entering the duodenum, or else isotonicity is dominant over pH in activating duodenal receptors which increase motor activity.3. When the pH of the isotonic NaCl was reduced by the addition of HCl to below pH 2.0, inhibition of gastric function occurred in direct proportion to the amount of titratable acid present in the infusate. The H(+) moiety of isotonic duodenal infusates of pH < 2.0 dominates activation of osmoreceptors and so inhibits motor activity.4. When the same amount of acid but at differing concentrations and infusion rates was introduced into the duodenum uniform inhibition of gastric function occurred. This result indicates that duodenal acid receptors respond to acid concentration and flow rate to produce an integrated response in proportion to the amount (concentration x volume) of acid present.5. Isotonic NaHCO(3) solutions adjusted to pH 8.1-12.0 by the addition of NaOH, like isotonic NaCl infusions, did not affect gastric function until pH 11.0-12.0, when significant inhibition occurred. This inhibitory effect of isotonic NaHCO(3) at high pH is probably due to CO(3) (2-), since Na(2)CO(3) and Li(2)CO(3), but not LiCl, produce a similar inhibitory effect on gastric function.6. The inhibitory effect of carbonate gives some support to the existence of a CO(2)-sensor as suggested by Hunt & Knox (1972), whereby increased P(CO2) produced by intracellular or intercellular neutralization of CO(3) (2-) by duodenal H(+) activates acid receptors. But other experiments reported here, where simultaneous perfusion of HCl and excess NaHCO(3) produced a rise in intraluminal P(CO2), did not inhibit gastric function, which is contrary to the idea of a direct intraluminal effect of CO(2) on duodenal receptors.7. The pH, P(O2), P(CO2), HCO(3) (-) and base excess of venous blood showed no detectable change during duodenal infusion of either acidic or alkaline solutions. Metabolic acidosis or alkalosis, therefore, cannot be considered to play any part in controlling gastric function. The results thus corroborate the notion that the receptors controlling gastric function are localized in the intestinal mucosa.8. Our results suggest that interplay between acid and osmolality of gastric chyme occurs in the rostral part of the duodenum to produce a graded inhibitory effect which by negative feedback modulates the gastric effectors that normally activate smooth muscle, parietal cells and zymogen cells.

Animals↗
PubMed2003

Store-operated Ca2+ entry: dynamic interplay between endoplasmic reticulum, mitochondria and plasma membrane.

In eukaryotic cells, hormones and neurotransmitters that engage the phosphoinositide pathway evoke a biphasic increase in intracellular free Ca2+ concentration: an initial transient release of Ca2+ from intracellular stores is followed by a sustained phase of Ca2+ influx. This influx is generally store-dependent and is required for controlling a host of Ca2+-dependent processes ranging from exocytosis to cell growth and proliferation. In many cell types, store-operated Ca2+ entry is manifest as a non-voltage-gated Ca2+ current called ICRAC (Ca2+ release-activated Ca2+ current). Just how store emptying activates CRAC channels remains unclear, and some of our recent experiments that address this issue will be described. No less important from a physiological perspective is the weak Ca2+ buffer paradox: whereas macroscopic (whole cell) ICRAC can be measured routinely in the presence of strong intracellular Ca2+ buffer, the current is generally not detectable under physiological conditions of weak buffering following store emptying with the second messenger InsP3. In this review, I describe some of our experiments aimed at understanding just why InsP3 is ineffective under these conditions and which lead us to conclude that respiring mitochondria are essential for the activation of ICRAC in weak intracellular Ca2+ buffer. Mitochondrial Ca2+ uptake also increases the dynamic range over which InsP3 functions as the second messenger that controls Ca2+ influx. Finally, we find that Ca2+-dependent slow inactivation of Ca2+ influx, a widespread but poorly understood phenomenon that helps shape the profile of an intracellular Ca2+ signal, is regulated by mitochondrial Ca2+ buffering. Thus, by enabling macroscopic store-operated Ca2+ current to activate and then by controlling its extent and duration, mitochondria play a crucial role in all stages of store-operated Ca2+ influx. Store-operated Ca2+ entry reflects therefore a dynamic interplay between endoplasmic reticulum, mitochondria and plasma membrane.

Animals↗
PubMed1997

An anisotropic biphasic theory of tissue-equivalent mechanics: the interplay among cell traction, fibrillar network deformation, fibril alignment, and cell contact guidance.

We present a general mathematical theory for the mechanical interplay in tissue-equivalents (cell-populated collagen gels): Cell traction leads to compaction of the fibrillar collagen network, which for certain conditions such as a mechanical constraint or inhomogeneous cell distribution, can result in inhomogeneous compaction and consequently fibril alignment, leading to cell contact guidance, which affects the subsequent compaction. The theory accounts for the intrinsically biphasic nature of collagen gel, which is comprised of collagen network and interstitial solution. The theory also accounts for fibril alignment due to inhomogeneous network deformation, that is, anisotropic strain, and for cell alignment in response to fibril alignment. Cell alignment results in anisotropic migration and traction, as modeled by a cell orientation tensor that is a function of a fiber orientation tensor, which is defined by the network deformation tensor. Models for a variety of tissue-equivalents are shown to predict qualitatively the alignment that arises due to inhomogeneous compaction driven by cell traction.

Anisotropy↗
PubMed2005

Confirmation, refinement, and extension of a study in intrafraction motion interplay with sliding jaw motion.

The interplay between a constant scan speed and intrafraction oscillatory motion produces interesting fluence intensity modulations along the axis of motion that are sensitive to the motion function, as originally shown in a classic paper by Yu et al. [Phys. Med. Biol. 43, 91-104 (1998)]. The fluence intensity profiles are explored in this note for an intuitive understanding, then compared with Yu et al., and finally further explored for the effects of low scan speed and random components of both intrafraction and interfraction motion. At slow scan speeds typical of helical tomotherapy, these fluence intensity modulations are only a few percent. With the addition of only a small amount of cycle-to-cycle randomness in frequency and amplitude, the fluence intensity profiles change dramatically. It is further shown that after a typical 30-fraction treatment, the sensitivities displayed in the single fraction fluence intensity profiles greatly diminish.

Body Burden↗
PubMed2006

In vitro and in vivo correlation of hepatic transporter effects on erythromycin metabolism: characterizing the importance of transporter-enzyme interplay.

The effects of hepatic uptake and efflux transporters on erythromycin (ERY) disposition and metabolism were examined by comparing results from rat hepatic microsomes, freshly isolated hepatocytes, and in vivo studies. Uptake studies carried out in freshly isolated rat hepatocytes showed that ERY and its metabolite (N-demethyl-ERY) are substrates of Oatp1a4 and Oatp1b2. Whereas rifampin and GG918 [GF120918: N-{4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)-ethyl]-phenyl}-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamine] exerted minimal effects on metabolism in microsomes, rifampin (2.5 microM) and GG918 (0.5 microM) significantly decreased and increased ERY metabolism in hepatocytes, respectively. Concentration-time course studies further demonstrated that, compared with the intracellular N-demethyl-ERY control area under the curve (AUC) (0.795 +/- 0.057 microM . min), a decreased AUC (0.513 +/- 0.028 microM . min, p < 0.005) was observed when ERY was coincubated with rifampin, and an increased AUC (2.14 +/- 0.21 microM . min, p < 0.05) was found when GG918 was present. The results of the i.v. bolus studies showed that, compared with the ERY clearance of the controls (47.2 +/- 12.5 ml/min/kg for the rifampin group and 42.1 +/- 5.7 for the GG918 group), a decreased blood clearance, 29.8 +/- 6.1 ml/min/kg (p < 0.05) and 21.7 +/- 9.0 ml/min/kg (p < 0.01), was observed when rifampin or GG918, respectively, was coadministered. When either inhibitor was codosed with ERY, volume of distribution at steady state was unchanged, but t1/2 and mean residence time significantly increased compared with the controls. Hepatic uptake and efflux transporters modulate intracellular concentrations of ERY, thereby affecting metabolism. The interplay of transporters and enzymes must be considered in evaluating potential drug-drug interactions.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

Coadministration of a liver X receptor agonist and a peroxisome proliferator activator receptor-alpha agonist in Mice: effects of nuclear receptor interplay on high-density lipoprotein and triglyceride metabolism in vivo.

Liver X receptors (LXRs) are master transcription factors regulating cholesterol and fatty acid metabolism. Treatment of C57B6 mice with a specific synthetic LXR agonist, N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1(trifluoromethyl)-ethyl]phenyl]-benzenesulfonamide (T0901317), resulted in elevated high-density lipoprotein (HDL) cholesterol as well as plasma and liver triglycerides. Peroxisome proliferator-activated receptor-alpha (PPARalpha) agonists are known to induce peroxisomal fatty acid beta-oxidation and also mediate HDL cholesterol metabolism. We have explored the hypothesis that simultaneous activation of PPARalpha and LXR may lead to additive effects on HDL cholesterol elevation as well as attenuation of triglyceride accumulation. Coadministration of T0901317 and the specific PPARalpha agonist [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid (Wy14643)] in mice led to synergistic elevation of HDL cholesterol that was primarily associated with enlarged HDL particles enriched with apoE and apoAI. Liver phospholipid transfer protein (PLTP) mRNA and plasma PLTP activity were additively elevated, suggesting a role of PLTP in the observed HDL cholesterol elevation. Moderate increases in plasma triglyceride levels induced by LXR activation was reduced, whereas the accumulation of triglyceride in the liver was not altered upon coadministration of the PPARalpha agonist. Peroxisomal fatty acid beta-oxidation in the liver was dramatically elevated upon PPARalpha activation as expected. Interestingly, activation of LXRs via T0901317 also led to a significant increase in peroxisomal fatty acid beta-oxidation. Sterol regulatory element binding protein 1c expression was dramatically up-regulated by the LXR agonist but was not changed with PPARalpha agonist treatment. Liver lipoprotein lipase expression was additively increased upon LXR agonist and PPARalpha agonist coadministration. Our studies mark the first exploration of nuclear receptor interplay on lipid homeostasis in vivo.

Animals↗
PubMed2004

Hepatobiliary disposition of the metabolically stable opioid peptide [D-Pen2, D-Pen5]-enkephalin (DPDPE): pharmacokinetic consequences of the interplay between multiple transport systems.

[D-Pen2,D-Pen5]-Enkephalin (DPDPE) is excreted extensively into the bile. Although DPDPE is transported by P-glycoprotein (P-gp), multidrug resistance-associated protein 2 (Mrp2) has been identified as an important mechanism for DPDPE transport across the canalicular membrane of the hepatocyte. The present studies determined the relative impact of Mrp2 and P-gp on the hepatobiliary disposition of [3H]DPDPE in isolated perfused rat livers (IPLs). Perfusate clearance of [3H]DPDPE was not different between livers from control and Mrp2-deficient (TR-) rats. Biliary excretion of [3H]DPDPE in IPLs from Wistar control rats was rapid and extensive. However, when [3H]DPDPE was administered to livers from TR- rats, the rate and extent of excretion decreased significantly. Surprisingly, in the presence of the P-gp inhibitor GF120918 [N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide], biliary excretion of [3H]DPDPE was not inhibited in control livers. In contrast, administration of GF120918 to TR- livers further reduced the maximal excretion rate and decreased net biliary excretion of [3H]DPDPE by 87%. GF120918 administration caused an unexpected increase in perfusate clearance in both control and TR- rat livers. At distribution equilibrium, [3H]DPDPE liver/perfusate partitioning was higher in GF120918-treated livers. Results of pharmacokinetic modeling were consistent with the hypothesis that GF120918 inhibited a [3H]DPDPE basolateral excretion mechanism. Mrp2 is the primary mechanism for [3H]DPDPE biliary excretion, and P-gp facilitates excretion of [3H]DPDPE only in the absence of functional Mrp2. [3H]DPDPE is a substrate for a basolateral efflux mechanism that is sensitive to inhibition by GF120918. These data emphasize the importance of using appropriate model systems and comprehensive pharmacokinetic modeling in elucidating the complex interplay between multiple transport systems.

Acridines↗
PubMed2006

Bias in estimation of transporter kinetic parameters from overexpression systems: Interplay of transporter expression level and substrate affinity.

The objective was to investigate the interplay between transporter expression levels and substrate affinity in controlling the influence of aqueous boundary layer (ABL) resistance on transporter kinetics in an over-expression system. Taurocholate flux was measured across human apical sodium-dependent bile acid transporter (hASBT)-Madin-Darby canine kidney monolayers on different occasions and kinetic parameters estimated with and without considering ABL. In error-free simulation/regression studies, flux values were generated across a range of J max, Kt, and substrate concentrations. Similar evaluation was performed for transport inhibition studies. Additionally, simulation/regression studies were performed, incorporating 15% random error to estimate the probability of successfully estimating Kt. Across different occasions, experimental J max and Kt estimates for taurocholate were strongly associated (p < 0.001; r2 = 0.82) when ABL was not considered. Simulation/regression results indicate that not considering ABL caused this association, such that Kt estimates were highly positively biased at high hASBT expression. In reanalyzing taurocholate flux data using the ABL-present model, Kt was relatively constant across occasions (approximately 5 microM) and not associated with J max (p = 0.24; r2 = 0.13). Simulations suggest that J max and Kt collectively determined ABL influence, which is most prominent under conditions of low monolayer resistance. Additionally, not considering ABL lead to negatively biased Ki estimates, especially at high J max. Error-inclusive simulation/regression studies indicated that the probability of successfully estimating Kt depended on the contribution of ABL resistance to flux; when flux became increasingly ABL-limited, probability of success decreased. Results indicate that ABL resistance can bias Kt and Ki estimates from overexpression systems, where the extent of bias is determined by transporter expression level and substrate affinity.

Animals↗
PubMed2002

Unmasking the dynamic interplay between intestinal P-glycoprotein and CYP3A4.

Drug efflux by intestinal P-glycoprotein (P-gp) is known to decrease the oral bioavailability of many CYP3A4 substrates. We hypothesized that the interplay occurring between P-gp and CYP3A4 at the apical membrane would increase the opportunity for drug metabolism. To define the roles of P-glycoprotein (P-gp) and CYP3A4 in controlling the extent of intestinal absorption and metabolism, two substrates were tested. The transport, metabolism, and intracellular levels of N-methyl piperazine-Phe-homoPhe-vinylsulfone phenyl (K77, a cysteine protease inhibitor; P-gp and CYP3A4 substrate) and felodipine (CYP3A4 substrate only) were measured across CYP3A4-transfected Caco-2 cells in the presence of an inhibitor of CYP3A4 and P-gp, cyclosporine (CsA), or an inhibitor of P-gp and not CYP3A4, GG918 (N-[4-[2-(1,2,3,4-tetrahydro-6,7- dimethoxy-2-isoquinolinyl)-ethyl]-phenyl]-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamine). The extent of metabolism was measured by calculating the extraction ratio (ER) across the cells, while accounting for intracellular changes occurring with P-gp inhibition. The (A)pical to (B)asolateral and B-->A ERs for K77 were 0.33 and 0.06, respectively. These changed with GG918 to 0.14 and 0.12 and with CsA to 0.06 and 0.04. Felodipine ERs were similar in both directions, 0.26 and 0.24 (A-->B and B-->A), and were unchanged in the presence of GG918 but decreased with CsA (0.14 and 0.11). The K77 absorption rate was increased 5 and 4.2-fold in the presence of CsA and GG918, respectively, whereas no change was observed for felodipine absorption. The decreased A-->B ER and increased absorption of K77 with GG918 suggest that P-gp influences the extent of drug metabolism in the intestine via prolonging the access of drugs to CYP3A4 near the apical membrane and decreasing transport across the cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1991

Interplay of cell wall barrier and beta-lactamase activity determines high resistance to beta-lactam antibiotics in Mycobacterium chelonae.

We calculated the target access index, which reflects the probability that a drug will reach its target at an effective concentration, and the predictive MICs of cephaloridine, cephalothin, and cefazolin for Mycobacterium chelonae from the drug concentrations inhibiting the binding of benzylpenicillin to penicillin-binding proteins, the permeability coefficients, and the beta-lactamase properties. Despite a low level of beta-lactamase activity and because of a very effective permeability barrier, the target access indices were very low, e.g., 100 times lower than for penicillinase-producing Escherichia coli. The predicted MICs were within one to three twofold dilutions of the experimentally determined values (which ranged between 512 and greater than or equal to 2,048 micrograms/ml). These results demonstrate that the interplay of the cell wall barrier and beta-lactamase activity determines high resistance of M. chelonae to beta-lactam antibiotics.

Cefazolin↗
PubMed1992

Interplay of impermeability and chromosomal beta-lactamase activity in imipenem-resistant Pseudomonas aeruginosa.

Mutational loss of the D2 porin causes imipenem resistance in Pseudomonas aeruginosa. It was found that this mechanism could function only when the chromosomal beta-lactamase was expressed. Mutants lacking both the beta-lactamase and the D2 porin were almost as susceptible as those that lacked the beta-lactamase but retained the porin. Thus, imipenem resistance reflected an interplay of the enzyme and impermeability, not either factor alone. These findings suggest that the activity of a carbapenem more beta-lactamase stable than imipenem should be less affected by the porin loss. Meropenem approached this behavior.

Bacterial Outer Membrane Proteins↗
PubMed1999

Interplay between chromosomal beta-lactamase and the MexAB-OprM efflux system in intrinsic resistance to beta-lactams in Pseudomonas aeruginosa.

We investigated the role of chromosomal beta-lactamase and the MexAB-OprM efflux system in intrinsic resistance to beta-lactams in Pseudomonas aeruginosa. Determination of the susceptibilities of a series of isogenic mutants with impaired production of the beta-lactamase and the efflux system to 16 beta-lactams including penicillins, cephems, oxacephems, carbapenems, and a monobactam demonstrated that the intrinsic resistance of P. aeruginosa to most of the beta-lactams is due to the interplay of both factors.

Drug Resistance, Microbial↗
PubMed2001

Pseudomonas aeruginosa reveals high intrinsic resistance to penem antibiotics: penem resistance mechanisms and their interplay.

Pseudomonas aeruginosa exhibits high intrinsic resistance to penem antibiotics such as faropenem, ritipenem, AMA3176, sulopenem, Sch29482, and Sch34343. To investigate the mechanisms contributing to penem resistance, we used the laboratory strain PAO1 to construct a series of isogenic mutants with an impaired multidrug efflux system MexAB-OprM and/or impaired chromosomal AmpC beta-lactamase. The outer membrane barrier of PAO1 was partially eliminated by inducing the expression of the plasmid-encoded Escherichia coli major porin OmpF. Susceptibility tests using the mutants and the OmpF expression plasmid showed that MexAB-OprM and the outer membrane barrier, but not AmpC beta-lactamase, are the main mechanisms involved in the high intrinsic penem resistance of PAO1. However, reducing the high intrinsic penem resistance of PAO1 to the same level as that of penem-susceptible gram-negative bacteria such as E. coli required the loss of either both MexAB-OprM and AmpC beta-lactamase or both MexAB-OprM and the outer membrane barrier. Competition experiments for penicillin-binding proteins (PBPs) revealed that the affinity of PBP 1b and PBP 2 for faropenem were about 1.8- and 1.5-fold lower, than the respective affinity for imipenem. Loss of the outer membrane barrier, MexAB, and AmpC beta-lactamase increased the susceptibility of PAO1 to almost all penems tested compared to the susceptibility of the AmpC-deficient PAO1 mutants to imipenem. Thus, it is suggested that the high intrinsic penem resistance of P. aeruginosa is generated from the interplay among the outer membrane barrier, the active efflux system, and AmpC beta-lactamase but not from the lower affinity of PBPs for penems.

Anti-Bacterial Agents↗
PubMed2006

Interplay of efflux system, ampC, and oprD expression in carbapenem resistance of Pseudomonas aeruginosa clinical isolates.

Carbapenems are important agents for the therapy of infections due to multidrug-resistant Pseudomonas aeruginosa; the development of carbapenem resistance hampers effective therapeutic options. To assess the mechanisms leading to resistance, 33 clinical isolates with differing degrees of carbapenem susceptibility were analyzed for the expression of the chromosomal beta-lactamase (ampC), the porin that is important for the entry of carbapenems (oprD), and the proteins involved in four efflux systems (mexA, mexC, mexE, and mexX). Real-time reverse transcriptase PCR was performed using primers and fluorescent probes for each of the target genes. The sequencing of regulatory genes (ampR, mexR, nalC, nalD, mexT, and mexZ) was also performed. Diminished expression of oprD was present in all imipenem- and meropenem-resistant isolates but was not required for ertapenem resistance. Increased expression of ampC was not observed in several isolates that were overtly resistant to carbapenems. Increased expression of several efflux systems was observed in many of the carbapenem-resistant isolates. Increased efflux activity correlated with high-level ertapenem resistance and reduced susceptibility to meropenem and aztreonam. Most isolates with increased expression of mexA had mutations affecting nalC and/or nalD. Two isolates with mutations leading to a premature stop codon in mexZ had markedly elevated mexX expressions, although mutations in mexZ were not a prerequisite for overexpression. beta-Lactam resistance in clinical isolates of P. aeruginosa is a result of the interplay between diminished production of oprD, increased activity of ampC, and several efflux systems.

Anti-Bacterial Agents↗