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At least 667 records · Page 37Linked to original sources
PubMed1985

A comparison of the in-vitro activity of some 5-nitroimidazoles and other compounds against Giardia intestinalis.

The activities of 11 5-nitroimidazole compounds have been compared against Giardia intestinalis in vitro using a 3H-thymidine incorporation assay. All the compounds were at least equipotent to, or more active than metronidazole with the exception of panidazole. Satranidazole, ronidazole and S75 0400 A were all about five times more active than metronidazole and warrant further study as potential chemotherapeutic agents for man. No major differences in the response to these compounds was found between two stocks of Giard. intestinalis with the exception of flunidazole. Several other antiprotozoal drugs showed activity against Giard. intestinalis. Berberine sulphate, paromomycin sulphate, erythromycin estolate and sulphasalazine, all of which have been used to treat human patients, showed no activity in vitro.

Giardia↗
PubMed1986

Aminoglycoside-phosphotransferases APH(3')-IV and APH(3") synthesized by a strain of Campylobacter coli.

Campylobacter coli strain 981 of animal origin was resistant to erythromycin, tetracycline, streptomycin, kanamycin, ribostamycin, neomycin, paromomycin, lividomycin, and butirosin. Resistance to aminoglycosides of strain 981 was mediated by phosphotransferases APH (3') type-IV and APH (3"). C. coli 981 harboured three plasmids of 24, 34, and 40 Megadaltons respectively. None of these plasmids were transferable to Escherichia coli K-12 by conjugation.

Aminoglycosides↗
PubMed1987

AAC(1): a new aminoglycoside-acetylating enzyme modifying the Cl aminogroup of apramycin.

An aminoglycoside-acetylating enzyme produced by a strain of Escherichia coli with an unusual resistance phenotype was characterized. This enzyme was found to mono-acetylate apramycin, butirosin, lividomycin and paromomycin and diacetylate ribostamycin and neomycin to give reaction products which were distinguishable by HPLC analysis from those of AAC(2'), AAC(3) and AAC(6') enzymes. The enzyme, however, was not found to acetylate amikacin, fortimicin, geneticin, gentamicin, kanamycin A, netilmicin or tobramycin. The reaction product from the action of this enzyme on apramycin was purified and identified by nuclear magnetic resonance studies as 1-N-acetyl apramycin. The second site at which ribostamycin and neomycin B were modified by this enzyme was not determined but is postulated as the 6'-amino group. It is proposed that this enzyme be named AAC(1).

Acetyltransferases↗
PubMed1996

Current therapeutic approaches to cryptosporidiosis in immunocompromised patients.

Cryptosporidium parvum is a protozon which can cause a severe debilitating disease in immunocompromised patients. Animal models show that cellular immunity is the most important factor protecting against the development of the disease, but patients with a humoral immune deficiency are also at risk. In HIV-infected patients there is a clear relationship between disease severity and CD4-cell counts. The development of insight into the pathogenesis and of new agents is hampered by the lack of an in-vitro culture system. Prevention is of utmost importance because of the difficulties of therapy and the severity of the clinical disease which can develop. Oocysts are highly resistant to the commonly used disinfectants. HIV-infected patients with cryptosporidiosis not on antiretroviral therapy should commence it. Non-specific therapy with anti-diarrhoeal agents should be instituted. If no effect is seen, therapy with paromomycin 500 mg qds for 2-3 weeks should be started, followed by maintenance therapy with 500 mg bid to prevent a relapse.

Animals↗
PubMed2006

Targeting the dimerization initiation site of HIV-1 RNA with aminoglycosides: from crystal to cell.

The kissing-loop complex that initiates dimerization of genomic RNA is crucial for Human Immunodeficiency Virus Type 1 (HIV-1) replication. We showed that owing to its strong similitude with the bacterial ribosomal A site it can be targeted by aminoglycosides. Here, we present its crystal structure in complex with neamine, ribostamycin, neomycin and lividomycin. These structures explain the specificity for 4,5-disubstituted 2-deoxystreptamine (DOS) derivatives and for subtype A and subtype F kissing-loop complexes, and provide a strong basis for rational drug design. As a consequence of the different topologies of the kissing-loop complex and the A site, these aminoglycosides establish more contacts with HIV-1 RNA than with 16S RNA. Together with biochemical experiments, they showed that while rings I, II and III confer binding specificity, rings IV and V are important for affinity. Binding of neomycin, paromomycin and lividomycin strongly stabilized the kissing-loop complex by bridging the two HIV-1 RNA molecules. Furthermore, in situ footprinting showed that the dimerization initiation site (DIS) of HIV-1 genomic RNA could be targeted by these aminoglycosides in infected cells and virions, demonstrating its accessibility.

Aminoglycosides↗
PubMed2002

Polypeptide synthesis directed by DNA as a messenger in cell-free polypeptide synthesis by extreme thermophiles, Thermus thermophilus HB27 and Sulfolobus tokodaii strain 7.

Polypeptide synthesis at high temperature directed by single strand DNA as a messenger was investigated using cell-free extracts of an extremely thermophilic bacterium, Thermus thermophilus strain HB27, and a hyperthermophilic, acidophilic archaeon, Sulfolobus tokodaii strain 7. Aminoglycoside antibiotics enhanced the reaction; neomycin stimulated it most effectively when the extract of the thermophilic bacterium was used, and paromomycin was the best among the antibiotics tested for the extract of the hyperthermophilic archaeon. A common correlation was found between the stimulation of DNA-directed polypeptide synthesis and the misreading rate in RNA-directed polypeptide synthesis. Spermine stimulated the reaction directed by DNA like in the case of poly(Phe) synthesis directed by poly (rU). The cell-free systems can be used for direct production of proteins from genes in high throughput studies on the structural genomics of thermophilus.

Cytidine Triphosphate↗
PubMed1989

Biochemical mechanisms of aminoglycoside cell toxicity. II. Accumulation of phospholipids during myeloid body formation and histological studies on myeloid bodies using twelve aminoglycoside antibiotics.

Cultured human skin fibroblasts take up aminoglycoside antibiotics into lysosomes to form myeloid bodies. Gentamicin (GM), one such antibiotic, was taken up until the cellular concentration reached an estimated 64 mM on the 3rd day when cells were incubated with 2 mM gentamicin. The rate of release of intracellular GM was high on the first day of incubation and gradually slowed down over the next 4 d. About 50% of the GM remained in the cells even on longer incubation in GM-free medium, suggesting it may irreversibly bind to cellular components. With myeloid body formation, the cellular phospholipid content increased 1.5 times. Bis(monoacyl-glyceryl)phosphate, which is known as a marker of lysosomal phospholipid, phosphatidylcholine and phosphatidylserine showed 250, 162, and 153% increases, respectively. Sphingomyelin was not accumulated, while lysosomal sphingomyelinase was dramatically inhibited. Of 12 different aminoglycoside antibiotics, paromomycin is the most prominent myeloid body-forming antibiotic. The myeloid body-formation is not directly correlated to human nephrotoxicity. On the other hand, the number of myeloid bodies is well correlated to the affinity to the brush border membrane, suggesting that such aminoglycoside antibiotics are taken up easily through cellular endocytosis. The cytotoxic effects of aminoglycoside antibiotics may be due to by their binding to cellular organelles other than lysosomes.

Anti-Bacterial Agents↗
PubMed1998

Recent advances in leishmaniasis.

There has been a rapid increase in the understanding of the mechanisms whereby Leishmania infects mammalian hosts and evades the immune response. This, in turn, is driving the search for vaccines against leishmaniasis. Leishmaniasis is an infection in which the dichotomy between cellular (T-helper cell type 1) and humoral (T-helper cell type 2) responses is clearly characterized in murine models, but is unclear in humans. The diagnosis of infection may be improved by use of the polymerase chain reaction and by serology using a recombinant antigen, K39. The therapeutic choice in visceral leishmaniasis is aided by recent studies of the lipid-associated amphotericin B drugs and aminosidine (paromomycin). Unfortunately, interferon-gamma, allopurinol, and topical aminosidine are all less effective treatments than was originally thought.

Journal Article↗
PubMed1999

Recent strategies for the chemotherapy of visceral leishmaniasis.

Visceral leishmaniasis is a widespread and deadly disease. First-line drugs are antimonials, but amphotericin B and its lipid formulations B is used for treating visceral leishmaniasis that is unresponsive to antimony. New therapeutic approaches are being actively developed, including the following: use of drug carriers targeted specifically to the parasite location, thus reduce adverse effects of drug; use of immunomodulating drugs; evaluation of natural products; pharmacokinetic studies; and drug combinations. Recent clinical trials with paromomycin and miltefosine were successful and these drugs appear to be promising for the future therapy of visceral leishmaniasis. Furthermore, identification and therapeutic evaluation of specific targets in the Leishmania organism could lead to new compounds, such as antileishmanial drugs and reversal agents of drug resistance.

Journal Article↗
PubMed2000

Treatment of gastrointestinal infections.

Treatment of gastrointestinal infections continues to be complicated by expanding resistance to antibiotics. This has led to both new antibiotic treatments and to research on alternative therapies. In the case of Clostridium difficile colitis, interesting preliminary results have been obtained with both probiotic therapy and passive immunization strategies. The newer macrolides were found to be effective for multidrug-resistant Salmonella typhi and safe in the pediatric population. The efficacy of rifaximin, a nonabsorbed antimicrobial agent, was demonstrated in the treatment of travelers diarrhea in Mexico. The benefit of the proteolytic agent bromelain, which degrades enterocyte receptors for enterotoxigenic Escherichia coli, was shown in an experimental model of piglets challenged with this infection after bromelain prophylaxis. The potential value of zinc supplementation in infant diarrhea was shown in a study in India. The recently approved rotavirus vaccine is being withheld because of multiple reported cases of intussusception. Cryptosporidiosis continues to challenge old and new chemotherapeutic agents. The usefulness of paromomycin in Cryptosporidium infection was shown in both murine and piglet models. The cost effectiveness of prophylaxis for parasitosis in immigrants has been an area of investigation.

Journal Article↗
PubMed2002

Update on protozoan parasites of the intestine.

The last year has seen new approaches to the diagnosis, treatment, and prevention of protozoal infections of the gastrointestinal tract. Some of the news is not good: new foodborne and swimming pool outbreaks of cyclosporiasis and cryptosporidiosis, respectively, occurred in North America; paromomycin was shown to be ineffective treatment for cryptosporidiosis; and these parasitic diseases continued to have a worldwide impact on human health. On the bright side, there were important advances in the understanding of the pathogenesis of cryptosporidiosis and the diagnosis of amebiasis and giardiasis, and some new leads on the treatment of cryptosporidiosis and refractory giardiasis. Finally, evidence was found of acquired mucosal immunity to amebiasis in Bangladeshi children, offering a guide for the development of an amebiasis vaccine. This review is not intended to be comprehensive, but contains a variety of articles that the authors hope will be of interest to the reader.

Journal Article↗
PubMed1997

Potential efficacy of fumagillin in intestinal microsporidiosis due to Enterocytozoon bieneusi in patients with HIV infection: results of a drug screening study. The French Microsporidiosis Study Group.

OBJECTIVE: Intestinal microsporidiosis due to Enterocytozoon bieneusi is a frequent cause of chronic diarrhoea in patients with HIV infection for which there is no available therapy. This study was designed to search for a drug with activity against this organism. DESIGN: Prospective open-labelled Phase II multicentre study. SETTING: University hospitals. PATIENTS: Sixty HIV-infected men with intestinal E. bieneusi infection. INTERVENTIONS: Ten drug regimens were consecutively tested orally for 3 weeks: albendazole plus metronidazole, sulphadiazine plus pyrimethamine, atovaquone, doxycycline plus nifuroxazide, itraconazole, flubendazole, chloroquine, paromomycin, sparfloxacin and fumagillin. Nine evaluable patients per regimen were required, but each patient could be enrolled up to three times in the study. OUTCOME MEASURE: Efficacy was assessed primarily by the clearance of E. bieneusi from stools and intestinal biopsies. The safety of each regimen was also assessed. RESULTS: Only purified fumagillin was able to clear E. bieneusi from stools as well as intestinal biopsies, whereas all other regimens failed to show antiparasitic efficacy. However, only four patients received fumagillin because of drug-induced thrombocytopenia. The four patients who received fumagillin remained free of E. bieneusi infection after a mean follow-up of 10 months. CONCLUSION: Eradication of E. bieneusi from the intestinal tract of patients with HIV infection and persistent immunosuppression is an achievable goal. Our study allowed the identification of oral fumagillin as a potential treatment for intestinal microsporidiosis due to E. bieneusi.

AIDS-Related Opportunistic Infections↗
PubMed1983

Identification of Tn2401, a transposon encoding multiresistance to aminoglycosides.

A transposable element, Tn2401, was found in a clinical isolate of Pseudomonas aeruginosa. Tn2401 had a size of 7190 nucleotides and encoded aminoglycoside 3'-phosphotransferase and aminoglycoside 6'-N-acetyltransferase. The sequence encoding the former enzyme was homologous with that of Tn903. Pseudomonas aeruginosa strains harbouring this transposon were resistant to kanamycin, neomycin, lividomycin, ribostamycin, paromomycin, netilmycin, tobramycin, dibekacin, gentamicin, sisomicin, and butirosin.

Acetyltransferases↗
PubMed1984

Resistance to apramycin in Escherichia coli isolated from animals: detection of a novel aminoglycoside-modifying enzyme.

The mechanisms of resistance to apramycin of five isolates of Escherichia coli from animals were investigated. Three isolates, which were resistant to all the aminoglycosides tested, did not transfer their resistance and did not produce aminoglycoside-modifying enzymes. The fourth isolate, which was resistant to apramycin, tobramycin, gentamicin, kanamycin and neomycin but not to amikacin, owed its resistance to production of the acetyltransferase AAC(3)IV. The gene specifying this enzyme was carried on a transposon, Tn800, on a plasmid designated R1535. The fifth isolate was resistant to apramycin, neomycin and kanamycin but not to gentamicin, tobramycin or amikacin. It produced an acetyltransferase that readily acetylated only apramycin, neomycin and paromomycin, a compound that is closely related to neomycin. Synthesis of this enzyme was specified by a chromosomal gene located near pyrD at about 20 min on the map of the E. coli K12 chromosome.

Acetyltransferases↗
PubMed2002

Identification of a role for Saccharomyces cerevisiae Cgr1p in pre-rRNA processing and 60S ribosome subunit synthesis.

Saccharomyces cerevisiae CGR1 encodes a conserved fungal protein that localizes to the nucleolus. To determine if this localization reflects a role for Cgr1p in ribosome biogenesis two yeast cgr1 mutants were examined for defects in ribosome synthesis: a conditional depletion strain in which CGR1 is under the control of a tetracycline-repressible promoter and a mutant strain in which a C-terminal truncated Cgr1p is expressed. Both strains had impaired growth rates and were hypersensitive to the aminoglycosides paromomycin and hygromycin. Polysome analyses of the mutants revealed increased levels of free 40S subunits relative to 60S subunits, a decrease in 80S monosomes and accumulation of half-mer polysomes. Pulse-chase labelling demonstrated that pre-rRNA processing was defective in the mutants, resulting in accumulation of the 35S, 27S and 7S pre-rRNAs and delayed production of the mature 25S and 5 small middle dot8S rRNAs. The synthesis of the 18S and 5S rRNAs was unaffected. Loss of Cgr1 function also caused a partial delocalization of the 5'-ITS1 RNA and the nucleolar protein Nop1p into the nucleoplasm, suggesting that Cgr1p contributes to compartmentalization of nucleolar constituents. Together these findings establish a role for Cgr1p in ribosome biogenesis.

Base Sequence↗
PubMed2003

Rubisco activase is required for optimal photosynthesis in the green alga Chlamydomonas reinhardtii in a low-CO(2) atmosphere.

This report describes a Chlamydomonas reinhardtii mutant that lacks Rubisco activase (Rca). Using the BleR (bleomycin resistance) gene as a positive selectable marker for nuclear transformation, an insertional mutagenesis screen was performed to select for cells that required a high-CO2 atmosphere for optimal growth. The DNA flanking the BleR insert of one of the high-CO2-requiring strains was cloned using thermal asymmetric interlaced-polymerase chain reaction and inverse polymerase chain reaction and sequenced. The flanking sequence matched the C. reinhardtii Rca cDNA sequence previously deposited in the National Center for Biotechnology Information database. The loss of a functional Rca in the strain was confirmed by the absence of Rca mRNA and protein. The open reading frame for Rca was cloned and expressed in pSL18, a C. reinhardtii expression vector conferring paromomycin resistance. This construct partially complemented the mutant phenotype, supporting the hypothesis that the loss of Rca was the reason the mutant grew poorly in a low-CO2 atmosphere. Sequencing of the C. reinhardtii Rca gene revealed that it contains 10 exons ranging in size from 18 to 470 bp. Low-CO2-grown rca1 cultures had a growth rate and maximum rate of photosynthesis 60% of wild-type cells. Results obtained from experiments on a cia5 rca1 double mutant also suggest that the CO2-concentrating mechanism partially compensates for the absence of an active Rca in the green alga C. reinhardtii.

Animals↗
PubMed1981

Effects of antibiotics, N-acetylaminoacyl-tRNA and other agents on the elongation-factor-Tu dependent and ribosome-dependent GTP hydrolysis promoted by 2'(3')-O-L-phenylalanyladenosine.

GTP hydrolysis on elongation factor (EF) Tu . ribosome complexes has been assayed in the presence of 2'(3')-O-L-phenylalanyladenosine (AdoPhe), i.e. the 3'-terminal portion of Phe-tRNAPhe. Several requirements of the reaction have been characterized. Maximal activity is observed at 60-120 mM NH4Cl and 5-15 mM magnesium acetate. The reaction requires the free sulfhydryl group of EF-Tu normally implicated in aminoacyl-tRNA binding. Intact EF-Tu cannot be replaced by a large tryptic fragment of EF-Tu (Mr 39,000) that retains the ability to bind guanosine nucleotides. The aminoglycoside antibiotics, neomycin C and several kanamycins and gentamicins, stimulate the AdoPhe-promoted GTPase. Surprisingly, however, other closely related antibiotics, like neomycin B, paromomycin and ribostamycin, are ineffectual, thus indicating subtle differences in the actions of these antibiotics. AcPhe-tRNAPhe, bound to the ribosomal A-site, stimulates the AdoPhe-promoted GTPase, but this compound or AcTyr-tRNATyr, present in unbound form, strongly inhibits the reaction. These results suggest that N-blocked aminoacyl-tRNAs form ternary complexes with EF-Tu . GTP, which have not been previously detected because of their low stability.

Anti-Bacterial Agents↗
PubMed1982

Increase of fidelity of polypeptide synthesis by spermidine in eukaryotic cell-free systems.

The mechanism of spermidine-induced increase of fidelity of polypeptide synthesis in a wheat germ cell-free system has been studied. It was found that the increase of fidelity in the presence of spermidine occurred mainly at the level of binding of aminoacyl-tRNA to ribosomes, that reduction of misreading was more marked at the 5'-base than at the 3'-base of the codon and that misreading caused by paromomycin and kanamycin C was not significantly decreased by spermidine. It was deduced from these results that spermidine inhibited low-frequency misreading more strongly than high-frequency misreading. In addition, spermidine was found to stimulate the rejection of non-cognate aminoacyl-tRNA mainly at an initial discrimination step during the binding of amino-acyl-tRNA to ribosomes, and slightly at a subsequent GTP-dependent discrimination step, the so-called proofreading step. In yeast, rabbit reticulocyte, and Artemia salina cell-free systems, spermidine was found to increase the fidelity of protein synthesis.

Animals↗