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PubMed1986

Synergy of fosfomycin with beta-lactam antibiotics against staphylococci and aerobic gram-negative bacilli.

Fosfomycin inhibits bacterial cell wall synthesis at the initial stage. It can act synergistically with beta-lactams. The effect of the combination of fosfomycin and selected penicillins and cephalosporins against staphylococci, Pseudomonas aeruginosa, Pseudomonas cepacia and selected Gram-negative bacteria was determined. Synergy was determined by agar dilution and checkerboard titration methods; synergy was defined as an FIC index less than or equal to 0.5 and partial synergy greater than 0.5 to 0.75. Concentrations of drugs used were those that would be reached in man by intravenous and oral routes. Fosfomycin combined with nafcillin and with cefotaxime against staphylococci showed synergy for most isolates. For methicillin-resistant Staphylococcus aureus, synergy or partial synergy was found for 90% of isolates. Synergy was less frequently found with Staphylococcus epidermidis. The MICs for S. aureus were reduced from greater than or equal to 32 micrograms/ml to less than or equal to 1 microgram/ml. Fosfomycin was synergistic with ticarcillin, piperacillin, azlocillin, ceftazidime, aztreonam and imipenem against 31 to 61% of P. aeruginosa. MICs were reduced from greater than or equal to 128 micrograms/ml to 8-32 micrograms/ml, depending upon the agent. Although fosfomycin acted synergistically with azlocillin, piperacillin and ceftazidime against some P. cepacia, most often there was an indifferent interaction and MICs were in the resistant range, greater than or equal to 128 micrograms/ml. The interaction of fosfomycin and ampicillin was synergistic against a number of strains of Enterobacteriaceae, Proteus vulgaris and Providencia rettgeri, yielding MICs in an achievable range. The combination of fosfomycin with beta-lactams may be clinically useful in selected situations, particularly for methicillin-resistant staphylococci and beta-lactam-resistant P. aeruginosa.

Anti-Bacterial Agents↗

PubMed1993

Vestibular and proprioceptive modulation of postural synergies in normal subjects.

One way of investigating different muscle synergies underlying human balance control is to assume that only 1 or 2 centrally preprogrammed synergies are available to reestablish upright stance when it is perturbed. According to this hypothesis, the many, apparently different, synergies elicited by rotation or translation of a support-surface on which test subjects stand, in fact, result from a modulation of muscle responses induced by different amplitudes of afferent inputs. To test this hypothesis, we probed the balance control of 16 normal subjects with 5 combinations of rotation and translation of the support surface. Each combination yielded a constant angle (3 or 4 degrees) and angular velocity (18 and 36 degrees/s, respectively) over the first 120 ms of ankle dorsiflexion but resulted in differing velocities of upper leg, trunk, and head movements. These first 120 ms of link movements and the resulting muscle responses were analysed for amplitude and timing modulation using 3 techniques. First, velocities of initial link movements and areas of muscle EMG activity were examined separately for the minimum number of descriptors, which would optimally describe the linear variation of the interlink amplitude synergy with respect to the amount of support-surface rotation or translation employed to perturb balance. Initial trunk angular velocity, which was highly correlated with head linear acceleration (r = 0.9), provided the first best descriptor of initial link movements. Ankle angular velocity provided the second descriptor because it was not correlated with trunk angular velocity. The amplitude modulation synergy of EMG responses could be characterised by the modulation of tibialis anterior and paraspinal muscles between 160 and 240 ms and by that of soleus between 80 and 120 ms after stimulus onset. The linear combination of these best descriptors of link movements and that for EMG response amplitudes changed continuously in an identical manner with changes in the stimulus combination. Second, multivariate linear correlations between the amplitudes of initial link velocities and muscle EMG response areas best describing the response amplitude synergy were examined. Several significant correlations (r > 0.6) were obtained between leg and trunk muscle activity 120 ms after stimulus onset and trunk, or upper leg angular velocity, or head linear velocity, prior to 120 ms. Finally, crosscorrelations between muscle responses were examined for consistent interlink timing synergies between muscle responses.(ABSTRACT TRUNCATED AT 400 WORDS)

Afferent Pathways↗

PubMed1982

Synergy among agents inhibiting granulocyte aggregation.

Recent evidence suggests complement (C) -stimulated granulocytes (PMNs) are important in a variety of diseases, including shock and myocardial infarction (MI). Corticosteroids inhibit PMN response to C and show promise in some studies of shock and MI, but their use has not become routine for several reasons. Synergy was sought among agents inhibiting PMN aggregation in vitro in response to activated C: methylprednisolone (MP), with a 50% inhibitory dose (AD50) of 0.6 mg/ml; ibuprofen (IBU), with AD50 of 1.0 mg/ml, and betahistine (BH), with AD50 of 1.6 mg/ml. Simultaneous use of all three agents produced 3.4-fold synergy; 3-fold synergy obtained between IBU + MP and IBU + BH, while 1.5-fold synergy was noted between MP + BH. Further, MP and IBU were at least additive in inhibiting .O2- generation by FMLP-stimulated PMNs and in blocking directed migration. In a preliminary in vivo test of this finding, cats were given MP and IBU--in known individually ineffective doses--immediately prior to coronary artery ligation. Neither MP nor the low dose of IBU chosen limited the size of the resultant MI, while both agents together reduced MI size by 42%. Synergy among these agents suggests that they inhibit PMN function of distinct cellular mechanisms (as yet not elucidated). Further, early in vivo results encourage speculation that such synergy might ultimately be exploited clinically, although such speculation must presently be regarded as preliminary.

Betahistine↗

PubMed1995

Detection of aminoglycoside-penicillin synergy against Enterococcus faecium using high-content aminoglycoside disks.

Thirty-seven Enterococcus faecium strains were screened for high-level aminoglycoside resistance with an agar diffusion test using high-content aminoglycoside disks (300 micrograms of streptomycin and 120 micrograms of gentamicin, tobramycin, kanamycin or amikacin). The inhibition zones obtained were correlated with results of time-kill penicillin-aminoglycoside synergy studies. An 11 mm breakpoint differentiated strains susceptible or resistant to the synergy of streptomycin plus penicillin. Irrespective of the inhibition zones obtained with tobramycin and kanamycin disks, Enterococcus faecium strains never showed synergy with penicillin in combination with these aminoglycosides. Penicillin-amikacin synergy cannot be predicted by the amikacin disks. Nevertheless, even though kanamycin disks do not predict penicillin-kanamycin synergy, they can be used to predict penicillin-amikacin synergy. In summary, high-content streptomycin, gentamicin and kanamycin disks can be used to predict the susceptibility of Enterococcus faecium strains to the synergistic combination of penicillin plus one of the aminoglycosides (streptomycin, gentamicin or amikacin, respectively).

Aminoglycosides↗

PubMed2002

Prehension synergies: effects of object geometry and prescribed torques.

We studied the coordination of forces and moments exerted by individual digits in static tasks that required balancing an external load and torque. Subjects ( n=10) stabilized a handle with an attachment that allowed for change of external torque. Thumb position and handle width systematically varied among the trials. Each subject performed 63 tasks (7 torque values x 3 thumb locations x 3 widths). Forces and moments exerted by the digit tips on the object were recorded. Although direction and magnitude of finger forces varied among subjects, each subject used a similar multidigit synergy: a single eigenvalue accounted for 95.2-98.5% of the total variance. When task parameters were varied, regular conjoint digital force changes (prehension synergies) were observed. Synergies represent preferential solutions used by the subjects to satisfy mechanical requirements of the tasks. In particular, chain effects in force adjustments to changes in the handle geometry were documented. An increased handle width induced the following effects: (a). tangential forces remained unchanged, (b). the same tangential forces produced a larger moment T (t), (c). the increased T (t) was compensated by a smaller moment of the normal forces T(n), and (d). normal finger forces were rearranged to generate a smaller moment. Torque control is a core component of prehension synergies. Observed prehension synergies are only mechanically necessitated in part. The data support a theory of hierarchical organization of prehension synergies.

Adult↗

PubMed2005

The emergence and disappearance of multi-digit synergies during force-production tasks.

We analyzed patterns of covariation among forces produced by the five digits of the human hand during tasks that required the production of a pattern of the total force consisting of ramp-up, constant force, and ramp-down segments with the time of the ramps ranging from 0 to 3000 ms. Patterns of the variance of the total force and the sum of the variances of individual digit forces were compared over sets of 12 trials at each task. The initiation of the ramp-up segment was associated with positive covariation of digit forces. Negative covariation among digit forces (force-stabilizing synergies) emerged after a critical time of 600-800 ms, which was only weakly dependent on the ramp time. These synergies persisted over the steady-state phase. A quantitative index of digit force covariation was introduced; it showed a drop about 100 ms before initiation of the ramp-down phase; we termed this phenomenon "anticipatory covariation" (ACV). The ramp-down phase was associated with rapid disappearance of the force-stabilizing synergy over a time period that ranged from 0 to 600 ms and scaled strongly with the duration of the force ramp. Thumb-virtual finger synergies showed qualitatively similar behavior to the multi-finger synergies (virtual finger is an imagined digit whose action is mechanically equivalent to the action of the four fingers). We conclude that abrupt changes in a time profile of total force are associated with transient destabilization of the total force. Changes in force-stabilizing synergies may occur in preparation to changes in the total force.

Adult↗

PubMed1999

Kinematic synergies and equilibrium control during trunk movement under loaded and unloaded conditions.

The aim of the present investigation was to study the adaptation of the kinematic synergy responsible for equilibrium control during upper trunk movements to a 10-kg load added to the subject's shoulders. Five adult subjects were asked to bend their upper trunk forward to an angle of 35 degrees and then to hold the final position for 3 s, first without any load and then with a 10-kg load fixed to their shoulders. The final anteroposterior CM positions 400 ms after the movement offset, the time course of the anteroposterior center of mass (CM) shift during the movement, the EMG pattern of the main muscles involved in the movement and the initial CP shift were studied under both unloaded and loaded conditions. The kinematic synergy was quantified by performing a principal components analysis on the hip, knee and ankle angle changes occurring during the movement. The results indicate that: (1) the final anteroposterior position of the CM changed little if at all in the presence of the additional load, and that the anteroposterior CM shift was minimized throughout the duration of the movement; (2) the kinematic synergy was still characterized, in the presence of the additional load, by a strong coupling between the angle changes, as indicated by the fact that the first principal component (PC1) accounted for more than 99% of the hip, knee and ankle joint movements. A change was observed, however, in the ratio between the angles: the ankle extension increased, thus compensating for the additional theoretical forward CM shift that the additional load could be expected to cause; (3) the lack of change in the initial backward CP shift observed under loaded condition as well as the lack of change of the initial agonist EMG bursts suggest that the initial feedforward control of the kinematic synergy was not affected in the presence of the additional load. An increase in the antagonist bursts, presumably reflecting an adaptation of the kinematic synergy, was observed during the late phase of the movement; and (4) it is concluded that the adaptation of the kinematic synergy to the load was due to a specific change in the feedback control during the braking phase of the movement which presumably increases the ankle joint extension and consequently causes an increased backward shift of the hip which compensates for the forward shift due to the load.

Adult↗

PubMed2002

Isolate-specific synergy in disease symptoms between cauliflower mosaic and turnip vein-clearing viruses.

Simultaneous infection of a plant by two viruses can cause more severe disease than is caused by infection with either virus alone. Such synergy may be due to effects on the replication of one virus by the second virus or to other causes. The tobamovirus turnip vein-clearing virus (TVCV), itself causing almost imperceptible symptoms in infected turnips, exacerbated symptoms of infection of turnip by the Cabbage S isolate of the caulimovirus cauliflower mosaic virus (CaMV). The synergy in symptom production was most evident in a reduced size of leaves, providing an objective measure of synergy. In contrast, synergy did not occur when the CM4-184 isolate of CaMV was used in combination with TVCV. Both isolates of CaMV increased the level of TVCV accumulated in leaves. TVCV did not increase the level of the Cabbage S CaMV isolate. The use of Cabbage S-CM4-184 chimeras revealed that a region critical for isolate synergy in stunting was within the coat protein gene and/or the 5' one third of the reverse transcriptase gene. We conclude that the disease symptom synergy between TVCV and Cabbage S CaMV is not caused by altered levels of accumulation of the viruses, but instead reflects subtle genetic interactions mapping to the ORF IV-ORF V region of CaMV DNA.

Brassica napus↗

PubMed2005

Muscle synergies involved in preparation to a step made under the self-paced and reaction time instructions.

OBJECTIVE: To investigate multi-muscle synergies during preparation to making a step and their changes with speed of stepping and method of step initiation, self-paced vs. reaction-time. METHODS: Standing healthy persons performed stepping tasks under 3 instructions, 'comfortably, self-paced', 'very quick, self-paced', and 'as fast as possible to a visual signal'. Electromyographic (EMG) signals of 10 postural muscles were recorded and analyzed. The participants also performed standard tasks associated with releasing a load. These trials were used to identify muscle groupings (M-modes) associated with shifts of the center of pressure (COP) and relations between small changes in the M-modes and COP shifts. The framework of the uncontrolled manifold hypothesis was used to partition the EMG variance across stepping trials into two components that kept constant and changed the COP coordinates in the anterior-posterior (AP) and medio-lateral (ML) directions. RESULTS: Muscle synergies stabilizing COP trajectories in both AP and ML directions were observed in both the stepping and supporting legs. The synergies tended to weaken and disappear close to the moment of take-off. They showed only minor differences across the 3 tasks. In contrast, mechanical and EMG characteristics of postural adjustments to stepping were significantly larger and showed higher rates of change during quick steps and steps under the reaction-time instruction. CONCLUSIONS: COP shifts associated with preparation to making a step are stabilized by multi-muscle synergies. These synergies are robust across stepping speed and methods of step initiation, self-paced and reaction-time. SIGNIFICANCE: Studies of multi-muscle postural synergies are important for understanding postural disorders in neurological patients and changes in postural strategies with age.

Adult↗

PubMed1999

Loss of antiallodynic and antinociceptive spinal/supraspinal morphine synergy in nerve-injured rats: restoration by MK-801 or dynorphin antiserum.

The co-administration of morphine at spinal (i.th.) and supraspinal (i.c.v.) sites to the same rat produces antinociceptive synergy, a phenomenon which may underlie the clinical analgesic utility of this drug. In animals with peripheral nerve injury, however, the antinociceptive potency and efficacy of i.th. morphine is significantly decreased. Here, the possible loss of spinal/supraspinal morphine antinociceptive synergy and relationship to elevation of spinal dynorphin content was studied. Ligation of lumbar spinal nerves resulted in elevated dynorphin in the ipsilateral lumbar and sacral spinal cord. In sham-operated rats supraspinal/spinal co-administration of morphine produced synergistic antinociception which was unaffected by i.th. MK-801 or dynorphin A((1-17)) antiserum. In nerve-injured rats, i.th. morphine was inactive against tactile allodynia and showed diminished in potency against acute nociception without supraspinal/spinal antinociceptive synergy. Antiserum to dynorphin A((1-17)) or the non-competitive NMDA antagonist MK-801 increased the antinociceptive potency of i.th. morphine, restored supraspinal/spinal morphine antinociceptive synergy and elicited a dose-related i.th. morphine antiallodynic action. These agents did not demonstrate antinociceptive or antiallodynic activity alone and did not alter morphine actions in sham-operated animals. The loss of spinal/supraspinal antinociceptive synergy and lack of antiallodynic activity of spinal morphine appear to be due to the elevation across multiple spinal segments of dynorphin following nerve injury. Pathological actions of elevated dynorphin may directly or indirectly modulate the NMDA receptor, result in a loss of supraspinal/spinal morphine synergy and may thus account for the decreased clinical analgesic efficacy of morphine in peripheral neuropathies.

Analgesics, Opioid↗

PubMed1995

Synergy between signal transduction pathways is obligatory for expression of c-fos in B and T cell lines: implication for c-fos control via surface immunoglobulin and T cell antigen receptors.

Expression of the protooncogene c-fos is controlled by three main regulatory pathways involving kinase C, cAMP, and calcium. Kinase C mediates its effects via phosphorylation of serum response factor (SRF) which interacts with the serum response element (SRE); cAMP and calcium mediate their effects via phosphorylation of CREB (cAMP regulatory element binding protein) presumably by activation of a protein kinase A or calmodulin-regulated kinase. We have examined the function of these elements in Burkitt's lymphoma cells (Ramos and Daudi) as well as a T lymphocytic cell line (Jurkat). We have found that stimulation of any one of these pathways alone has little or no effect on c-fos induction. However, kinase C activation (PMA stimulation) combined with either cAMP (forskolin plus MIX) or calcium stimulation (ionophore) leads to greatly enhanced c-fos induction. By contrast, cAMP in the presence of calcium shows no synergy in c-fos induction. Okadaic acid augments PMA- as well as calcium-mediated activation of c-fos, and has little or no effect when combined with cAMP. The main difference between Ramos (B cells) and Jurkat (T cells) in the regulation of c-fos is that cAMP plus calcium is strongly synergistic in Jurkat and is without effect in Ramos. Analysis of AP-1 activity using gel mobility shift assays confirms that the requirements for synergy in c-fos mRNA induction are paralleled by requirements for synergy in induction of AP-1 activity. Signaling in B cells due to anti-Ig stimulation involves both kinase C activation and release of intracellular calcium, and results in c-fos mRNA induction. Our results indicate that synergy between the kinase C activation and calcium is needed for efficient c-fos induction since neither of these two alone induces c-fos well. That synergy of signaling pathways is relevant for the anti-Ig induction of c-fos is supported by the fact that cAMP-inducing agents and okadaic acid further enhance anti-Ig induction of c-fos. These results suggest that cell-specific patterns of synergy are an essential feature for c-fos induction and may be relevant for c-fos control through B and T cell antigen receptors.

Antibodies, Anti-Idiotypic↗

PubMed2005

Inhibition of phosphorolysis catalyzed by HIV-1 reverse transcriptase is responsible for the synergy found in combinations of 3'-azido-3'-deoxythymidine with nonnucleoside inhibitors.

In spite of the growing attention to the combined chemotherapy in the treatment of AIDS, the molecular mechanisms underlying the antiviral synergy of combinations of reverse transcriptase (RT) inhibitors are in most cases unknown. Most combinations of nonnucleoside inhibitors (NNRTI) with nucleoside analogues synergistically inhibit HIV-1 replication in cell culture, though they fail to show synergy in enzymatic assays. In this work we have examined the mechanisms mediating the synergy in combinations of AZTTP with NNRTIs on HIV-1 RT and their possible relevance in antiretroviral therapy. We found that if two inhibitors bind either to different sites on the RT or to the same site but to different mechanistic forms, it is always possible to find conditions in which their combination results in synergistic inhibition of DNA polymerase activity. Though these analyses are interesting from a biochemical point of view, this kind of synergy is unlikely to play any role in vivo, since this positive interaction is lost under the conditions present in viral replication. Here we describe that the synergy found for combinations of NNRTI with AZT is due not to the inhibition of the DNA polymerase activity but to the inhibition of the RT-catalyzed phosphorolysis by the NNRTI. While phosphorolytical removal of the AZT-terminated primer has been related to the mechanism of resistance toward AZT, our data suggest that a basal phosphorolysis occurs even with the wild-type enzyme, and that the inhibition of this activity could explain the synergy found in antiviral assays.

Alkynes↗

PubMed1999

Utilization of exogenous folate in the human malaria parasite Plasmodium falciparum and its critical role in antifolate drug synergy.

The antifolate combination pyrimethamine/sulphadoxine (PYR/SDX; Fansidar) is frequently used to combat chloroquine-resistant malaria. Its success depends upon pronounced synergy between the two components, which target dihydrofolate reductase (DHFR) and dihydropteroate synthetase (DHPS) in the folate pathway. This synergy permits clearance of parasites resistant to either drug alone, but its molecular basis is still unexplained. Plasmodium falciparum can use exogenous folate, which is normally present in vivo, bypassing SDX inhibition of DHPS and, apparently, precluding synergy under these conditions. However, we have measured parasite inhibition by SDX/PYR combinations in assays in which folate levels are strictly controlled. In parasites that use exogenous folate efficiently, SDX inhibition can be restored by levels of PYR significantly lower than those required to inhibit DHFR. Isobolograms show that the degree of synergy between PYR and SDX is highly dependent upon prevailing folate concentrations and are indicative of PYR acting to block folate uptake and/or utilization. No significant synergy was observed at physiological drug levels when PYR/SDX acted on purified DHFR, whether wild type or mutant. We conclude that the primary basis for antifolate synergy in these organisms arises from PYR targeting a site (or sites) in addition to DHFR, which restores DHPS as a relevant target for SDX.

4-Aminobenzoic Acid↗

PubMed2000

Taste preference synergy between glutamate receptor agonists and inosine monophosphate in rats.

Monosodium glutamate (MSG) elicits a taste called umami and interacts synergistically with nucleotide monophosphates such as 5'-inosine monophosphate (IMP) to potentiate this taste intensity. Indeed, the synergistic interaction of nucleotide monophosphates and MSG is a hallmark of umami. We examined interactions between MSG and other taste stimuli, including IMP, by measuring the lick rates of non-deprived rats during 30 s trials. To control for non-linear psychophysical functions, the concentration of one taste stimulus in a binary mixture was systematically increased while the concentration of the second taste stimulus was decreased (stimulus substitution method). Synergy between two stimuli was detected if the lick rate for a binary mixture exceeded that expected from the sum of the lick rates for each stimulus alone. In initial experiments, taste synergy was observed when rats were presented with mixtures of MSG and IMP but not with mixtures of MSG and sucrose. In subsequent experiments, glutamate receptor agonists other than MSG were presented with IMP to test for taste synergy. No evidence of synergy was seen when rats were presented with mixtures of IMP and kainic acid or IMP and N:-methyl-D-aspartate. However, taste synergy between IMP and L-AP4, a potent agonist at mGluR4 receptors, was observed. These results suggest that a metabotropic glutamate receptor similar to mGluR4 may be involved in the taste synergy that characterizes umami.

Animals↗

PubMed1983

Synergy with double and triple antibiotic combinations compared.

Combinations of two sets of antibiotics (gentamicin-carbenicillin-rifampicin and trimethoprim/sulphamethoxazole-carbenicillin-rifampicin) were tested against isolates of Pseudomonas maltophilia. An abbreviated checker-board method permitted tests with combinations of all three antibiotics and of each of the possible three pairs in each set. Triple combinations were usually synergistic, whereas 25% of combinations of pairs were antagonistic or additive. The modal degree of synergy was greater with combinations of three antibiotics than with combinations of any two. For any isolate, greater synergy was generally obtained with a triple than with a double combination, and the mean degree of synergy was always greater with triple than with double combinations. It was advantageous to add to double combinations even an antibiotic to which the organism was resistant. Organisms multiply resistant to three antibiotics were also resistant to 25% of combinations of pairs, but never resistant to combinations of all three. Synergy was more likely to be present at all antibiotic ratios with triple than with double combinations. Since ratios at the site of action may differ greatly from that of the administered combination, there would be substantial clinical benefit in identifying sets of antibiotics of which combinations at all ratios showed synergy. The search for these may entail exploring multicomponent combinations and, with conventional methods, this raises a considerable logistic problem. A strategy is therefore proposed, designed to find antibiotic sets showing synergy at all ratios.

Anti-Bacterial Agents↗

PubMed1991

Synergy with cefsulodin or piperacillin and three aminoglycosides or aztreonam against aminoglycoside resistant strains of Pseudomonas aeruginosa.

Fifty-one strains of Pseudomonas aeruginosa, with resistance to one or more amino-glycosides, were tested for synergy with cefsulodin or piperacillin plus amikacin, tobramycin, gentamicin or aztreonam by the agar dilution technique. Cefsulodin plus any one of the three aminoglycosides regardless of the degree of resistance to the aminoglycoside was synergistic against P. aeruginosa for two thirds of the isolates. In contrast, synergy rates with piperacillin were much less uniform. The highest rate of synergy with piperacillin (90.0%) was observed with gentamicin for the gentamicin resistant strains. The lowest rate of synergy was observed with piperacillin plus amikacin (32.2%) for isolates with moderate resistance to amikacin. Synergy for strains with moderate resistance to amikacin was observed more commonly with cefsulodin than with piperacillin. Synergy for strains with a known mechanism of resistance to amikacin was more common with cefsulodin regardless of the mechanism of resistance. Cefsulodin or piperacillin in combination with aztreonam was rarely synergistic (less than 12%).

Aminoglycosides↗

PubMed1989

In vitro activities of quinolones against enterococci resistant to penicillin-aminoglycoside synergy.

The MICs and MBCs of CI-934, ciprofloxacin, difloxacin (A-56619), A-56620, norfloxacin, enoxacin, amifloxacin, and coumermycin were determined for 43 clinical isolates of Enterococcus faecalis known to be resistant to penicillin-aminoglycoside synergy. Results were compared with those obtained for 37 synergy-susceptible E. faecalis and 22 Enterococcus faecium strains. Although no substantial differences in quinolone activities were observed between synergy-resistant and -susceptible E. faecalis strains, CI-934 and ciprofloxacin were the drugs that demonstrated the greatest bactericidal activity against both types of E. faecalis. The MBCs of the other quinolones were generally within a single twofold dilution of the MICs, but their antienterococcal activity did not approach that of CI-934 or ciprofloxacin. The MBCs for 90% of the isolates of CI-934 for synergy-resistant and -susceptible E. faecalis strains were 1 and less than or equal to 0.5 microgram/ml, respectively. The ciprofloxacin MBC for 90% of the E. faecalis strains tested was 1 microgram/ml. For E. faecium isolates the CI-934 and ciprofloxacin MBCs for 90% of the isolates were 8 and 4 micrograms/ml, respectively. Time-kill assays performed with synergy-susceptible enterococcal strains showed that the bactericidal activities of both CI-934 and ciprofloxacin were less than those of the penicillin-aminoglycoside combinations tested. However, against synergy-resistant isolates the activities of these two quinolones were comparable with and sometimes greater than those of penicillin-aminoglycoside combinations.

4-Quinolones↗

PubMed1998

Transcription factor Pip can enhance DNA binding by E47, leading to transcriptional synergy involving multiple protein domains.

The transcription factors E2A (E12/E47) and Pip are both required for normal B-cell development. Each protein binds to regulatory sequences within various immunoglobulin enhancer elements. Activity of E2A proteins can be regulated by interactions with other proteins which influence their DNA binding or activation potential. Similarly, Pip function can be influenced by interaction with the protein PU.1, which can recruit Pip to bind to DNA. We show here that a previously unidentified Pip binding site resides adjacent to the E2A binding site within the immunoglobulin kappa 3' enhancer. Both of these binding sites are crucial for high-level enhancer activity. We found that E47 and Pip can functionally interact to generate a very potent 100-fold transcriptional synergy. Through a series of mutagenesis experiments, we identified the Pip sequences necessary for transcriptional activation and for synergy with E47. Two synergy domains (residues 140 to 207 and 300 to 420) in addition to the Pip DNA binding domain (residues 1 to 134) are required for maximal synergy with E47. We also identified a Pip domain (residues 207 to 300) that appears to mask Pip transactivation potential. Part of the synergy mechanism between E47 and Pip appears to involve the ability of Pip to increase DNA binding by E47, perhaps by inducing a conformational change in the E47 protein. E47 may also induce a conformational change in Pip which unmasks sequences important for transcriptional activity. Based upon our results, we propose a model for E47-Pip transcriptional synergy.

3T3 Cells↗