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PubMed1983

Genetic effects on the longevity of cultured human fibroblasts. III. Correlations with altered glucose-6-phosphate dehydrogenase.

The level of heat-labile glucose-6-phosphate dehydrogenase (G6PD) has been measured in skin fibroblast cultures from premature ageing or DNA repair deficient genetic syndromes. The short in vitro longevity of Werner's syndrome, progeria, Cockayne's syndrome, ataxia telangiectasia, Fanconi's anaemia, and Bloom's syndrome cultures was correlated with the appearance of a significant fraction of heat-labile enzyme. Long-lived control cultures contain a low level of altered enzyme until they become senescent. The evidence that heat-labile G6PD molecules are derived from errors in synthesis, or from other causes, is critically assessed. It is shown that normal cells grown in medium containing the antibiotic, paromomycin, which is known to reduce the fidelity of ribosomal translation, produce a significant fraction of altered G6PD.

Aged↗
PubMed1995

Aminoglycoside resistance in Haemophilus influenzae.

From September 1, 1990 to December 31, 1993 a total of 425 Haemophilus influenzae strains from clinical specimens were isolated in the Microbiology Laboratory of the Zaragoza University Hospital. Of these strains, 16 (33.33%) were resistant to kanamycin, neomycin, paromomycin, lividomycin and streptomycin. Demonstration of APH (3')-I activity by the phosphocellulose paper binding assay, based on the incorporation of radiolabel into lividomycin was sixfold greater than into butirosin. Two DNA probes were prepared to screen for the genes encoding APH(3') activity in kanamycin-resistant H. influenzae. Homology was observed between the aphA1 DNA probe and total cellular DNA from all 16 APH(3')-I producers. On the other hand, streptomycin-resistance was not through metabolic modification of the antibiotic.

Anti-Bacterial Agents↗
PubMed2004

Purine bases at position 37 of tRNA stabilize codon-anticodon interaction in the ribosomal A site by stacking and Mg2+-dependent interactions.

The anticodon loop of tRNA contains a number of conserved or semiconserved nucleotides. In most tRNAs, a highly modified purine is found at position 37 immediately 3' to the anticodon. Here, we examined the role of the base at position 37 for tRNA(Phe) binding to the A site of Escherichia coli ribosomes. Affinities and rate constants of A-site binding of native yeast peptidyl-tRNA(Phe) with hypermodified G (wybutine), or of unmodified peptidyl-tRNA(Phe) transcripts with G, A, C, or U, at position 37 were measured. The data indicate that purines stabilize binding due to stronger stacking and additional interactions with the ribosome mediated by Mg(2+) ions. Paromomycin, an antibiotic that binds to 16S rRNA in the decoding center, greatly stabilized tRNAs in the A site and abolished the Mg(2+)-dependence of binding. Comparison of binding enthalpies and entropies suggests that hypermodification of the base at position 37 does not affect stacking in the codon-anticodon complex, but rather decreases the entropic penalty for A-site binding. Substitution of purines with pyrimidines at position 37 increases the rates of tRNA binding to and dissociation from the A site. The data suggest that initial binding of tRNA to the A site is followed by a rate-limiting rearrangement of the anticodon loop or the ribosome decoding center that is favored by purines at position 37 and involves stronger stacking, additional Mg(2+) binding, and interactions with 16S rRNA.

Anti-Bacterial Agents↗
PubMed2003

Long-lasting anticryptosporidial activity of nitazoxanide in an immunosuppressed rat model.

Cryptosporidium parvum, Tyzzer, 1912 is identified as a common cause of diarrhoea in immunocompetent individuals. In immunocompromised, especially HIV-infected subjects, cryptosporidiosis causes severe chronic diarrhoea. In this study, nitazoxanide (NTZ) was compared for curative activity with sinefungin (SNF) and paromomycin (PRM) in immunosuppressed rats, a screening model for anticryptosporidial agents. NTZ at either 50 mg/kg/day, 100 mg/kg/day or 200 mg/kg/day resulted in seven days in a dose-dependent inhibition of oocyst shedding similar to that obtained with SNF (10 mg/kg/day) and PRM (100 mg/kg/day). Further discontinuation of SNF or PRM 100 mg/kg/day therapy resulted in early relapse of oocyst shedding which reached the pre-treatment levels in 2-4 days. In contrast, seven days after discontinuation of therapy, shedding inhibition was unchanged in NTZ-treated rats. Data prompt further assessment of the activity of NTZ on sequestered C. parvum.

Adenosine↗
PubMedDate not supplied

Therapeutic trial in experimental tegumentary leishmaniasis caused by Leishmania (Leishmania) amazonensis. A comparative study between mefloquine and aminosidine.

One hundred and eighty-two male inbred C57/BL/6 mice were infected with 3 x 10(6) Leishmania (Leishmania) amazonensis promastigotes of the MHOM/BR/PH8 strain by means of a subcutaneous injection in the right ear. The animals were separated in three groups: 1) oral mefloquine hydrochloride treatment (16 mg/kg/day/10 days), 2) intramuscular aminosidine (Paromomycin) treatment (20 mg/kg/20 days) and 3) control. Twenty-six mice of each treated group were sacrificed, one at the end of treatment (nine weeks after inoculation), and one six weeks later (fifteen weeks after inoculation). Control Group animals were sacrificed at weeks six, nine and fifteen after inoculation. There was no significant difference between Group 1 (mefloquine) and Group 3 (control) subjects. Group 2 animals (aminosidine) presented the smallest differences of all, both at the end of the treatment and six weeks later. The histopato-logical parameters have shown the following findings: a) there was no significant difference between the mefloquine treated group and the control group; the group treated with aminosidine showed fewer of vacuolated macrophages than the control group, at week 9 (end of treatment). b) both at the end of treatment and six weeks later, evaluation of tissue necrosis and tissue fibrosis revealed no differences between the treated groups. It was found that six weeks after the end of treatment, mice in the control group presented significantly more severe degrees of fibrosis than mice in the other groups. It can be concluded that mefloquine showed limited therapeutic effect in this experimental model, whereas aminosidine had a significant effect. Nevertheless, neither of them resulted in cure of the lesions.

Animals↗
PubMed2004

Outcome of cats with diarrhea and Tritrichomonas foetus infection.

OBJECTIVE: To determine the long-term outcome of cats infected with Tritrichomonas foetus and identify treatment and management strategies influencing resolution of infection or associated diarrhea. DESIGN: Prospective study. SAMPLE POPULATION: 26 cats with T. foetus-associated diarrhea at least 22 months prior to the study. PROCEDURE: A standardized survey regarding clinical course and management was administered to owners of cats with T. foetus infection and associated diarrhea. Fecal samples were obtained from each cat; the presence of T. foetus was assessed via microscopic examination of smears, culture in commercial media, and polymerase chain reaction amplification of T. foetus rDNA involving species-specific primers. RESULTS: Survey responses were obtained from owners of all 26 cats. Twenty-three cats had complete resolution of diarrhea a median of 9 months after onset. Analysis of fecal samples obtained from 22 cats revealed persistent T. foetus infection in 12, with a median of 39 months after resolution of diarrhea. History of implementation of a dietary change, treatment with paromomycin, or higher numbers of cats in the household was associated with significantly longer duration of time to resolution of diarrhea. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested chronic T. foetus-associated diarrhea in most cats is likely to resolve spontaneously within 2 years of onset. Chronic infection with T. foetus (without clinical signs) after resolution of diarrhea appears to be common. Although often temporarily effective in decreasing severity of diarrhea, attempts to treat cats with T. foetus infection may result in prolongation of time to resolution of diarrhea.

Animals↗
PubMed2002

Human infection with Cryptosporidium felis: case report and literature review.

An infection with Cryptosporidium felis in an HIV-positive man from Italy was successfully treated with paromomycin, despite the patient's having a CD4+ cell count of 31/mL. Fourteen cases of human infection with C. felis have been described, all in the past 3 years, emphasizing the public health importance of Cryptosporidium parasites other than C. parvum.

Adult↗
PubMed1992

Leishmania major: bacterial contamination of cutaneous lesions in experimental animals.

No bacterial contamination has been demonstrated in cutaneous leishmaniasis (CL) nodule and in lesions caused by Leishmania major in Balb/c mice up to 20 days after infection. However, although many phagocytic cells (polymorphonuclear leukocytes and macrophages) were present in the CL lesion, 80% of the lesions showed bacterial contamination that developed within the first 70 days of infection. Topical treatment of the lesion with an ointment containing 15% paromomycin and 12% methylbenzethonium chloride in soft white paraffin for 20 days eliminated all the Leishmania parasites and several of the associated bacteria including: Proteus vulgaris, Pasteurella multocida, Staphylococcus albus and Staphylococcus aureus. This treatment did not affect Escherichia coli, Klebsiella spp. and Pseudomonas aeruginosa. Total elimination of these bacteria was achieved only during the healing process, and within 20 days following termination of treatment. The rate of disappearance of bacteria inoculated alone into the base of the tail of normal uninfected Balb/c mice was much faster than that of bacteria inoculated into either the CL nodule or the CL lesion. This study suggests the development of local immunosuppression in the CL lesion that may be mediated by the Leishmania parasites and their metabolites.

Animals↗
PubMed2004

[Outbreak of amoebiasis in a Dutch family; tropics unexpectedly nearby].

An amoebic liver abscess, amoebic dysentery and asymptomatic cyst passage were diagnosed in a father, a mother and one of their three children, respectively. One of the other children had been in the tropics, but only after the father's symptoms had begun. All three family members were infected with the same strain of Entamoeba histolytica as determined by polymerase chain reaction (PCR)-based DNA typing. The source of infection was most probably in Southern Italy where the family regularly spent their summer holidays. All three infected patients recovered after drug treatment. In a patient with a liver abscess or colitis, amoebiasis should be considered even in the absence of a history of a stay in the tropics. Stool samples should be examined for amoebic cysts and trophozoites. PCR analysis of parasite DNA extracted directly from stool samples makes differentiation between the morphologically identical cysts of E. histolytica and the non-pathogenic Entamoeba dispar possible. In addition, serum antibodies to E. histolytica are almost always present in symptomatic patients. Invasive infections with E. histolytica require treatment with a tissue amoebicidal drug, followed by a contact amoebicide to prevent recurrence. Currently, paromomycin is considered to be the first-line luminal amoebicide because of its efficacy and safety.

Adolescent↗
PubMed2005

Translational readthrough of a termination codon in the yeast mitochondrial mRNA VAR1 as a result of mutation in the release factor mRF1.

Yeast mitochondrial DNA codes for eight major polypeptides. Translation of he mitochondrially encoded polypeptides in strains with mutated mitochondrial release factor, mRF1, was found to result in the synthesis of a novel protein, V2. Different mrf1 alleles were associated with different efficiency of V2p synthesis. Translation of V2p was enhanced by paromomycin. Comparative analysis of peptides resulting from protease digestion indicated that V2p is a derivative of Var1p. According to our hypothesis, V2p represents a readthrough product of the natural stop codon in VAR1 mRNA.

Codon, Terminator↗
PubMed2006

Visceral leishmaniasis (kala-azar): challenges ahead.

Indian visceral leishmaniasis (VL) is a parasitic disease caused by a haemoflagellete Leishmania donovani and transmitted by the bite of sand fly Phlebotomus argentipes. It affects various age groups. In India about 1,00,000 cases of VL are estimated to occur annually; of these, the State of Bihar accounts for over than 90 per cent of the cases. Diagnosis of VL typically relies on microscopic examination of tissue smears but serology and molecular methods are better alternatives currently. Notwithstanding the growing incidence of resistance, pentavalent antimony complex has been the mainstay for the treatment of VL during the last several decades. The second line drugs such as amphotericin B, lipid formulations of amphotericin B, paromomycin and recently developed miltefosine are the other alternatives. In spite of significant development in various areas of Leishmania research, there is a pressing need for the technological advancement in the understanding of immune response, drug resistance and the pathogenesis of leishmaniasis that could be translated into field applicable and affordable methods for diagnosis, treatment, and control of the disease.

Aminoquinolines↗
PubMed1987

Aminoglycoside antibiotic treatment of human fibroblasts: intracellular accumulation, molecular changes and the loss of ribosomal accuracy.

The aminoglycoside antibiotic, G418, was rapidly endocytosed by human fibroblasts. The endocytic uptake comprised two phases. A rapid phase in which G418 was first adsorbed to the cell surface, followed by a slower rate of uptake of 7 to 11 micrograms/mg cell protein/24 h. The rapid uptake was independent of temperature and a fluorescent derivative of G418 could be seen bound to the cell surface. This evidence suggests a nonspecific adsorption mechanism. The slower rate of accumulation may arise from fluid-phase pinocytosis. The effects of G418 and paromomycin on protein synthesis in vivo and in vitro were compared and it was concluded that G418 was more active on mammalian ribosomes. Finally, changes in the pattern of cellular proteins during treatment with either aminoglycoside were found only with G418. The changes in the pattern of proteins suggest the synthesis of stress proteins in treated cells. This change in pattern may be interpreted as a cellular response to abnormal protein synthesis arising from a loss of fidelity or some inhibitory function of G418 on membrane metabolism which may lead to a shortening of cellular life span.

Anti-Bacterial Agents↗
PubMed1967

Antibiotic therapy of cholera.

Recent clinical trials having established the value of tetracycline as an adjunct to fluid and electrolyte replacement in cholera treatment, a controlled trial of antibiotic therapy was conducted in Dacca on 318 adults hospitalized for cholera. The effects of 4 antibiotics orally administered in varying dosage schedules were studied.Cholera therapy with tetracycline or chloramphenicol caused a highly significant reduction in the duration of diarrhoea and of positive culture, in stool volume, and in intravenous fluid requirement as compared with the results in controls who received intravenous fluid therapy only. Streptomycin was also effective, but to a lesser degree; paromomycin was of little value.The severity of dehydration on admission was significantly related to subsequent duration of diarrhoea regardless of whether antibiotics were given. Increasing age was associated with more prolonged purging in patients receiving antibiotics.Increasing the dose of tetracycline to 2 to 3 times that usually administered, or prolonging treatment from 2 to 4 days, did not enhance the therapeutic results. The effect of tetracycline was apparent within a few hours of administration. Bacteriological relapses were seen after discontinuation of therapy in all treatment groups, but were not due to the development of resistant bacteria.

Adolescent↗
PubMed1967

Antibiotic therapy of cholera in children.

In a controlled trial of the effects of oral antibiotics in treating cholera in children in Dacca, East Pakistan, tetracycline was the most effective of 4 antibiotics tested in reducing stool volume, intravenous fluid requirement, and the duration of diarrhoea and positive stool culture. Increasing the duration of tetracycline therapy from 2 to 4 days, or increasing the total dose administered, resulted in shorter duration of positive culture, but did not affect stool volume or duration of diarrhoea. Only 1% of the children receiving tetracycline had diarrhoea for more than 4 days. Tetracycline was significantly more effective than intravenous fluid therapy alone, regardless of severity of disease.Chloramphenicol, while also effective, was inferior to tetracycline. Streptomycin and paromomycin exerted little or no effect on the course of illness or duration of positive culture. Therapeutic failures with these drugs were not due to the development of bacterial resistance.From these findings, tetracycline appears to be the drug of choice against Vibrio cholerae infection in children. Oral therapy for 48 hours is effective clinically, but is associated with 20% bacteriological relapses when the drug is discontinued; it is not known whether extending the therapy for a week or more would eliminate such relapses.

Anti-Bacterial Agents↗
PubMed1996

Mof4-1 is an allele of the UPF1/IFS2 gene which affects both mRNA turnover and -1 ribosomal frameshifting efficiency.

The mof4-1 (maintenance of frame) allele in the yeast Saccharomyces cerevisiae was isolated as a chromosomal mutation that increased the efficiency of -1 ribosomal frameshifting at the L-A virus frameshift site and caused loss of M1, the satellite virus of L-A. Here, we demonstrate that strains harboring the mof4-1 allele inactivated the nonsense-mediated mRNA decay pathway. The MOF4 gene was shown to be allelic to UPF1, a gene whose product is involved in the nonsense-mediated mRNA decay pathway. Although cells harboring the mof4-1 allele of the UPF1 gene lose the M1 virus, mutations in other UPF genes involved in nonsense-mediated mRNA decay maintain the M1 virus. The mof4-1 strain is more sensitive to the aminoglycoside antibiotic paromomycin than a upf1 delta strain, and frameshifting efficiency increases in a mof4-1 strain grown in the presence of this drug. Further, the ifs1 and ifs2 alleles previously identified as mutations that enhance frameshifting were shown to be allelic to the UPF2 and UPF1 genes, respectively, and both ifs strains maintained M1. These results indicate that mof4-1 is a unique allele of the UPF1 gene and that the gene product of the mof4-1 allele affects both -1 ribosomal frameshifting and mRNA turnover.

Alleles↗
PubMed2004

Readthrough of dystrophin stop codon mutations induced by aminoglycosides.

We report the translational readthrough levels induced by the aminoglycosides gentamicin, amikacin, tobramycin, and paromomycin for eight premature stop codon mutations identified in Duchenne's and Becker's muscular dystrophy patients. In a transient transfection reporter assay, aminoglycoside treatment results show that one stop codon mutation is suppressed significantly better (up to 10% stop codon readthrough) than the others; five show lower but statistically significant suppression (< 2% stop codon readthrough); and two appear refractory to aminoglycoside treatment. Readthrough levels do not substantially vary between different sources of gentamicin, and, for this set of mutations, the efficiency of termination at the premature stop codon mutation does not appear to correlate with disease severity.

Aminoglycosides↗
PubMed1988

Californium-252 plasma desorption mass spectrometry of aminoglycoside antibiotics.

This paper presents mass spectral data of eleven aminoglycoside antibiotics by using californium-252 plasma desorption (252Cf PD) mass spectrometry. This mass spectral data could be used to develop a confirmatory method for monitoring aminoglycoside antibiotic residues isolated from food products of animal origin. Mass spectra were determined by applying time-of-flight 252Cf PD mass spectrometry to eleven aminoglycoside antibiotics, namely: neomycin, kanamycin, paromomycin, tobramycin, apramycin, streptomycin, dihydrostreptomycin, amikacin, netilmicin, sisomicin and gentamicins. All eleven antibiotics yielded positive ion spectra. These hydrophilic antibiotics were derivitized to extractable chromopheric compounds. All but two antibiotics (streptomycin and dihydrostreptomycin) yielded nitrophenyl derivatives and spectra were obtained in both negative and positive ion modes. Derivatized aminoglycosides produced cation and anion spectra with quasimolecular ions corresponding to [M + H]+., M+, [M - H]-., [M + Na]+, [M + K]+ and M-. or [M - H]- and M-. or [M - H]-. Underivatized antibiotics were best examined in the positive ion mode. 252Cf PD mass spectrometry consistently produced very strong molecular or quasimolecular ions for all aminoglycoside antibiotics.

Aminoglycosides↗
PubMed2003

The molecular basis for A-site mutations conferring aminoglycoside resistance: relationship between ribosomal susceptibility and X-ray crystal structures.

Aminoglycoside antibiotics target the 16S ribosomal RNA (rRNA) bacterial A site and induce misreading of the genetic code. Point mutations of the ribosomal A site may confer resistance to aminoglycoside antibiotics. The influence of bacterial mutations (introduced by site-directed mutagenesis) on ribosomal drug susceptibility was investigated in vivo by determination of minimal inhibitory concentrations. To determine the origin of the various resistance phenotypes at a molecular level, the in vivo results were compared with the previously published crystal structures of paromomycin, tobramycin, and geneticin bound to oligonucleotides containing the minimal A site. Two regions appear crucial for binding in the A site: the single adenine residue at position 1408 and the non-Watson-Crick U1406.U1495 pair. The effects of mutations at those positions are modulated by the nature of the substituent at position 6' (either hydroxy or ammonium group) on ring I, by the number of positive charges on the antibiotic, and by the linkage between rings I and III (either 4,5 or 4,6). In particular, the analysis demonstrates: 1) that the C1409-G1491 to A1409-U1491 polymorphism (observed in 15 % of bacteria) is not associated with resistance, which indicates that it does not affect the stacking of ring I on residue 1491, 2) that the high-level resistance to 6'-NH3+ aminoglycosides exhibited by the A1408G mutation most probably results from the inability of ring I forming a pseudo base pair with G1408, which prevents its insertion inside the A site helix, and 3) that mutations of the uracil residues forming the U1406.U1495 pair either to cytosine or to adenine residues mostly confer low to moderate levels of drug resistance, whereas the U1406C/U1495A double mutation confers high-level resistance (except for neomycin), which suggests that aminoglycoside binding to the wild-type A site and its functional consequences strongly depend on a particular geometry of the U1406.U1495 pair. The relationships between the resistance phenotypes observed in vivo and the interactions described at the molecular level define the biological importance of the different structural interactions observed by X-ray crystallography studies.

Aminoglycosides↗