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PubMed1985

Characteristics of the binding of aminoglycoside antibiotics to teichoic acids. A potential model system for interaction of aminoglycosides with polyanions.

The binding of the aminoglycoside antibiotic dihydrostreptomycin to defined cell-wall teichoic acids and to lipoteichoic acid isolated from various gram-positive eubacteria was followed by equilibrium dialysis. Dihydrostreptomycin was used at a wide range of concentration under different conditions of ionic strength, concentration of teichoic acid, presence of cationic molecules like Mg2+, spermidine, other aminoglycoside antibiotics (gentamicin, neomycin, paromomycin). Interaction of dihydrostreptomycin with teichoic acid was found to be a cooperative binding process. The binding characteristics seem to be dependent on structural features of teichoic acid and are influenced by cationic molecules. Mg2+, spermidine and other aminoglycosides antibiotics inhibit the binding of dihydrostreptomycin to teichoic acid competitively. The binding of aminoglycosides to teichoic acids is considered as a model system for the interaction of aminoglycoside antibiotics with cellular polyanions. Conclusions of physiological significance are drawn.

Aminoglycosides↗
PubMed1988

Modifications of oxidative phosphorylations in mitochondria isolated from a mutant of Saccharomyces cerevisiae. Possible alterations of the phosphate transport.

Mutants of Saccharomyces cerevisiae were isolated which supported two unlinked nuclear mutations conferring thermosensitivity and cold sensitivity respectively, and a mitochondrial one conferring paromomycin sensitivity. Mitochondria isolated from such a mutant exhibited modifications of several phosphate-requiring functions: (a) kinetic parameters of the phosphate dependence of ATP synthesis were modified; (b) in the absence of phosphate the inner mitochondrial membrane exhibited a high proton leakage; (c) mutant mitochondria always exhibited a poor respiratory control and required tenfold more phosphate to reach a maximal state 3 of respiration; (d) phosphate transport, as measured by swelling experiments, was mersalyl-insensitive and, consequently, state 3 of the respiration and ATP synthesis remained less mersalyl-sensitive than in wild-type mitochondria. Analysis of the mitochondrial metabolism of diploid and segregant strains indicates that these modifications are related to the cryosensitive phenotype; however, at present, a cooperative effect of the mitochondrial mutation cannot be eliminated. It is proposed that the phosphate carrier itself or a regulatory element was modified.

Adenosine Triphosphate↗
PubMed1995

Development of a microtitre ELISA to quantify development of Cryptosporidium parvum in vitro.

An in situ enzyme-linked immunosorbent assay (ELISA) was developed to evaluate growth of Cryptosporidium parvum in vitro. Ninety-six-well tissue culture microtitre plates were each seeded with 4.0 x 10(4) human ileocecal adenocarcinoma (HCT-8) cells, then infected with CsCl-purified oocysts 24 h later. The growth medium consisted of RPMI 1640 supplemented with 10% fetal bovine serum, 15 mM HEPES (N-2-hydroxyethylpiperazine N'-2-ethanesulfonic acid), 50 mM glucose, 1 microgram ml-1 folic acid, 4 micrograms ml-1 4-aminobenzoic acid, 2 micrograms ml-1 pantothenic acid and 35 micrograms ml-1 ascorbic acid. Incubation conditions were at 37 degrees C in a 5% CO2/95% humidified air incubator. Oocysts were allowed to excyst in situ so that sporozoites could infect cells directly. Monolayers were then washed, new medium added, and infected cells re-incubated. Levels of infection were assessed 48 h later using a rat anti-C. parvum polyvalent antiserum directed against purified parasite membranes, followed by a goat anti-rat IgG conjugated to horseradish peroxidase and 3,3',5,5'-tetramethyl-benzidine as substrate. Using various parasite inoculating doses and incubation times, optimal results were obtained using a 90-min exposure of host cells to 2.5-3.0 x 10(4) oocysts/well. Evaluation of various concentrations of four anti-microbials (monensin, lasalocid, paromomycin and sulfadimethoxine) in the system resulted in the acquisition of precise dose-response curves for each compound.

Animals↗
PubMed1996

A chemiluminescence immunoassay for evaluation of Cryptosporidium parvum growth in vitro.

A chemiluminescence immunoassay (CLIA) was developed to detect Cryptosporidium parvum growth in Madin-Darby canine kidney (MDCK) cell cultures. Optimal results were obtained when MDCK cells were plated at a density of 1 x 10(4) cells/well (96-well plate) and maintained as a monolayer for 4 days prior to infection with 2 x 10(4) parasites/well. Two compounds (paromomycin and maduramicin) were evaluated and shown to have selective activity against C. parvum in a dose-dependent manner. There was excellent correlation between CLIA and immunofluorescence assay when assessing anti-C. parvum agents in MDCK cells. CLIA offers advantages over conventional enzyme-linked immunosorbent assay and immunofluorescence assay methods in that it is more sensitive and efficient. The combination of CLIA and MDCK culture provides an efficient tool for evaluating potential anti-cryptosporidial compounds prior to testing in animal models.

Animals↗
PubMed1996

Acanthamoeba keratitis in the south of Sweden.

Eight patients with Acanthamoeba keratitis were diagnosed and treated at our clinic between February 1991 and February 1993. Five of these were contact lens wearers, two had suffered recent corneal trauma and one had recently undergone penetrating keratoplasty. The diagnoses were based on both culture and histological examination of biopsy material in three cases, on culture alone in two cases and on histological examination alone in three cases. In all but one primary treatment was Propamidine isethionate and Neomycin/Polymyxin B topically and Ketoconazole orally. Because of poor healing three patients additionally received Paromomycin and Miconazole or Clotrimazol topically; two of these were further treated with Polyhexamethylene biguanide topically. The interval from initial symptoms to accurate diagnoses varied from one to eleven months. In one patient the eye could not be saved; in the remaining patients visual acuity after healing ranged from hand movements to 1.0.

Acanthamoeba↗
PubMedDate not supplied

Infection with Cryptosporidium hominis and reinfection with Cryptosporidium parvum in a transplanted ileum.

A transplanted ileum was found to be infected with Cryptosporidium hominis 6 days after transplantation. Although the infection resolved, the ileum was later found to be infected with Cryptosporidium parvum. The presence of the parasite was not always correlated with diarrhea. No other gastrointestinal symptom was ever detected. Treatment with azithromycin and paromomycin apparently failed.

Adolescent↗
PubMed1986

Resistance of Candida parapsilosis to drugs.

Several strains of Candida parapsilosis, isolated independently in our laboratory, had their resistance compared to a series of inhibitors which act either at the level of mitochondrial ribosomes (chloramphenicol, erythromycin, paromomycin) or at the level of mitochondrial respiration and oxidative phosphorylation (oligomycin, antimycin A, diuron, carbonylcyanide m-chlorophenylhydrazone). Cells were grown on glycerol media supplemented with one of these inhibitors, and it was demonstrated that the resistance of these yeasts to a large spectrum of antibiotics was due to several features: a resistance to oligomycin was found at the permeation level; the resistance to the other drugs was correlated to the relative insensitivity of cytochrome biosynthesis to the drugs; the cells developed, at the same time, two types of alternative pathways: the one branched at the ubiquinone level which drove electrons from Krebs cycle substrates to oxygen, and the other, antimycin A-insensitive but inhibited by amytal, salicylhydroxamic acid and high cyanide concentrations. This secondary mitochondrial pathway, driving reducing equivalents from cytoplasmic NADH to cytochrome c and then to cytochrome aa3 or to alternate oxidase, allowed the growth of Candida parapsilosis on a non fermentescible medium, supplemented with these drugs.

Antimycin A↗
PubMed2006

Aph(3')-IIc, an aminoglycoside resistance determinant from Stenotrophomonas maltophilia.

We report the characterization of an intrinsic, chromosomally carried aph(3')-IIc gene from Stenotrophomonas maltophilia clinical isolate K279a, encoding an aminoglycoside phosphotransferase enzyme that significantly increases MICs of kanamycin, neomycin, butirosin, and paromomycin when expressed in Escherichia coli. Disruption of aph(3')-IIc in K279a results in decreased MICs of these drugs.

Aminoglycosides↗
PubMed1976

Enzymatic adenylylation by aminoglycoside 4'-adenylytransferase and 2"-adenylyltransferase as a means of determining concentrations of aminoglycoside antibiotics in serum.

A fast and accurate enzymatic estimation of the concentration of aminoglycoside antiobiotics in serum is given by aminoglycoside 4'-adenylyltransferase (synonym: tobramycin adenylyltransferase), a new enzyme recently found in tobramycin-resistant staphylococci (P. Santanam and F. H. Kayser, J. Infect. Dis. [Suppl.], in press). This enzyme is useful in assaying the kanamycins, the butirosins, amikacin, ribostamycin and, if required, the neomycins, tobramycin, and paromomycin. In combination with the assay using aminoglycoside 2''-adenylyltransferase (synonym: gentamicin adenylyltransferase) to determine the level of gentamicin, sisomicin, and tobramycin, a convenient method to estimate a wide range of aminoglycoside antibiotics in patients' sera is described.

Aminoglycosides↗
PubMed1978

Interaction of neomycin with ribosomes and ribosomal ribonucleic acid.

Neomycin binds ribosomes and ribosomal ribonucleic acid (rRNA) in vivo and in vitro producing changes detectable by increases in gel electrophoretic mobility. These changes were observed in gels that contain ethylenediaminetetraacetic acid or no added magnesium ion. The progressive increase in gel electrophoretic mobility with increasing antibiotic concentrations suggests that neomycin is binding at multiple sites on RNA. The binding was reversible but sufficiently stable to survive dialysis and electrophoresis. It is proposed that bound neomycin stabilizes the ribosome and RNA structures, restricting the unfolding of the particles during electrophoresis and thus allowing for a more rapid migration in the gel. Gentamicin produced an effect similar to that of neomycin. Paromomycin, differing from neomycin by only one amino group, had considerably less effect on ribosome and rRNA mobilities. The binding of neomycin to rRNA improved the linearity of the plot of log molecular weight versus mobility and thus may be of benefit in providing a more accurate estimation of molecular weights of large RNAs.

Anti-Bacterial Agents↗
PubMed1982

Ribosomal resistance in the gentamicin producer organism Micromonospora purpurea.

The mechanism of resistance of the gentamicin-producing organism Micromonospora purpurea was analyzed. Determination of minimal inhibitory concentrations revealed high resistance to the 4,6-substituted deoxystreptamine aminoglycosides amikacin, gentamicin, kanamycin, netilmicin, sisomicin, and tobramycin and also to lividomycin A and hygromycin B, but susceptibility to streptomycin, dihydrostreptomycin, paromomycin, and neomycin during all phases of the growth cycle. The nonproducing, closely related Micromonospora melanosporea was susceptible to these compounds. In agreement with results from previous studies (R. Benveniste and J. Davies, Proc. Natl. Acad. Sci. U.S.A. 70:2276-2280, 1973), extracts from M. purpurea showed no activity of enzymes specifically modifying gentamicin. 70S ribosomes from M. purpurea but not from M. melanosporea were resistant to inhibition by gentamicin, kanamycin, tobramycin, and lividomycin in a polyuridylic acid-dependent polyphenylalanine synthesis system and susceptible to those compounds which were inhibitory in vivo. The former antibiotics were also unable to induce misreading. Subunit exchange experiments between M. purpurea and M. melanosporea showed that the main site for inhibition and induction of misreading is the 30S subunit (up to gentamicin concentrations of 10 micrograms/ml).

Aminoglycosides↗
PubMed1984

Development of topical treatment for cutaneous leishmaniasis caused by Leishmania major in experimental animals.

Topical treatment, with drug-containing ointments, of cutaneous leishmaniasis caused by Leishmania major in BALB/c mice was studied. Twenty chemotherapeutic agents having potential or established antileishmanial activity were formulated in different ointment and cream bases. Only 15% paromomycin sulfate with 12% methylbenzethonium chloride, 12% benzethonium chloride, 12% cetalkonium chloride, or 12% dimethyl sulfoxide, all incorporated in white soft paraffin (United Kingdom patent application no. 2117237A), were completely effective. Topical treatment twice daily for 6 or more days caused total elimination of the parasites and healing of the lesion in all treated mice. All the other antileishmanial compounds, including sodium stibogluconate, pentamidine, amphotericin B, emetine hydrochloride, metronidazole, co-trimoxazole, allopurinol, and rifampin, either showed a slight effect on the parasites or were highly toxic to the animal host at the concentrations tested.

Administration, Topical↗
PubMed1990

Molecular analysis of a gentamicin resistance transposonlike element on plasmids isolated from North American Staphylococcus aureus strains.

Plasmid-encoded resistance to the aminoglycosides gentamicin (Gm), tobramycin (Tm), and kanamycin (Km) (GmTmKmr) in strains of Staphylococcus aureus isolated in Australia and North America appears to be mediated by one resistance determinant. In Australian isolates, this determinant is flanked by inverted copies of a 1.3-kb insertion sequence, IS256, thereby forming a composite transposon, Tn4001. Analysis of two conjugative plasmids and a related nonconjugative plasmid from strains of S. aureus isolated in North America showed that the GmTmKmr determinant on these plasmids is also flanked by inverted repeats. In the nonconjugative plasmid, these repeats include only 425 bp of IS256 immediately adjacent to the GmTmKmr region and identical to that on Tn4001. This truncated Tn4001 element is flanked by copies of the insertion element IS257, and together these elements form a truncated Tn4001-IS257 hybrid transposonlike structure. A third copy of IS257 was located 418 bp from the hybrid structure. The truncated Tn4001 and three repeats of IS257 were present at a conserved site on the plasmids studied. Four additional copies of IS257 were identified on the two conjugative plasmids. These elements flank determinants for resistance to the aminoglycosides neomycin and paromomycin and to ethidium bromide and quaternary ammonium compounds, as well as the region involved in conjugative plasmid transfer.

Amino Acid Sequence↗
PubMed1994

In vitro model to assess effect of antimicrobial agents on Encephalitozoon cuniculi.

We have developed a new micromethod to study the effect of drugs on microsporidia, using MRC5 fibroblasts infected by 10(5) spores of Encephalitozoon cuniculi. After 3 days of incubation with various concentrations of drugs, parasitic foci were counted in stained cultures. The inhibition of microsporidial growth exceeding 90% with albendazole (0.005 microgram/ml), fumagillin (0.001 microgram/ml), 5-fluorouracil (3 micrograms/ml), and sparfloxacin (30 micrograms/ml) was observed. Chloroquine, pefloxacin, azithromycin, and rifabutin were partially effective, at high concentrations. Arprinocid, metronidazole, minocycline, doxycycline, itraconazole, and difluoromethylornithine were not evaluable, since concentrations that inhibited microsporidia were also toxic for fibroblasts. Pyrimethamine, piritrexim, sulfonamides, paromomycin, roxithromycin, atovaquone, and flucytosine were ineffective. Our results confirm that albendazole and fumagillin have marked activity against E. cuniculi and show the antimicrosporidial activity of 5-fluorouracil and sparfloxacin. These data may form the basis for treatment of Encephalitozoon hellem and Septata intestinalis infections and represent an attempt to identify drugs effective against Enterocytozoon bieneusi.

Animals↗
PubMed1997

An axenic amastigote system for drug screening.

Currently available primary screens for selection of candidate antileishmanial compounds are not ideal. The choices include screens that are designed to closely reflect the situation in vivo but are labor-intensive and expensive (intracellular amastigotes and animal models) and screens that are designed to facilitate rapid testing of a large number of drugs but do not use the clinically relevant parasite stage (promastigote model). The advent of successful in vitro culture of axenic amastigotes permits the development of a primary screen which is quick and easy like the promastigote screen but still representative of the situation in vivo, since it uses the relevant parasite stage. We have established an axenic amastigote drug screening system using a Leishmania mexicana strain (strain M379). A comparison of the 50% inhibitory concentration (IC50) drug sensitivity profiles of M379 promastigotes, intracellular amastigotes, and axenic amastigotes for six clinically relevant antileishmanial drugs (sodium stibogluconate, meglumine antimoniate, pentamidine, paromomycin, amphotericin B, WR6026) showed that M379 axenic amastigotes are a good model for a primary drug screen. Promastigote and intracellular amastigote IC50s differed for four of the six drugs tested by threefold or more; axenic amastigote and intracellular amastigote IC50s differed by twofold for only one drug. This shows that the axenic amastigote susceptibility to clinically used reference drugs is comparable to the susceptibility of amastigotes in macrophages. These data also suggest that for the compounds tested, susceptibility is intrinsic to the parasite stage. This contradicts previous hypotheses that suggested that the activities of antimonial agents against intracellular amastigotes were solely a function of the macrophage.

Animals↗
PubMed1998

Efficacy of nitazoxanide against Cryptosporidium parvum in cell culture and in animal models.

Nitazoxanide (NTZ), a drug currently being tested in human clinical trials for efficacy against chronic cryptosporidiosis, was assessed in cell culture and in two animal models. The inhibitory activity of NTZ was compared with that of paromomycin (PRM), a drug that is partially effective against Cryptosporidium parvum. A concentration of 10 microg of NTZ/ml (32 microM) consistently reduced parasite growth in cell culture by more than 90% with little evidence of drug-associated cytotoxicity, in contrast to an 80% reduction produced by PRM at 2,000 microg/ml (3.2 mM). In contrast to its efficacy in vitro, NTZ at either 100 or 200 mg/kg of body weight/day for 10 days was ineffective at reducing the parasite burden in C. parvum-infected, anti-gamma-interferon-conditioned SCID mice. Combined treatment with NTZ and PRM was no more effective than treatment with PRM alone. Finally, NTZ was partially effective at reducing the parasite burden in a gnotobiotic piglet diarrhea model when given orally for 11 days at 250 mg/kg/day but not at 125 mg/kg/day. However, the higher dose of NTZ induced a drug-related diarrhea in piglets that might have influenced its therapeutic efficacy. As we have previously reported, PRM was effective at markedly reducing the parasite burden in piglets at a dosage of 500 mg/kg/day. Our results indicate that of all of the models tested, the piglet diarrhea model most closely mimics the partial response to NTZ treatment reported to occur in patients with chronic cryptosporidiosis.

Animals↗
PubMed2001

Aminoglycoside resistance with homogeneous and heterogeneous populations of antibiotic-resistant ribosomes.

Aminoglycosides bind to rRNA in the small subunit of the bacterial ribosome. Mutations in the decoding region of 16S rRNA confer resistance to specific subsets of aminoglycoside antibiotics. The two major classes of 2-deoxystreptamine aminoglycosides are the 4,5- and the 4,6-disubstituted antibiotics. Antibiotics of the 4,5-disubstituted class include neomycin, paromomycin, and ribostamycin. Gentamicins and kanamycins belong to the 4,6-disubstituted class of aminoglycosides. Structural studies indicated the potential importance of position 1406 (Escherichia coli numbering) in the binding of ring III of the 4,6-disubstituted class of aminoglycosides to 16S rRNA. We have introduced a U1406-to-A mutation in a plasmid-encoded copy of E. coli 16S rRNA which has been expressed either in a mixture with wild-type ribosomes or in a strain in which all rRNA is transcribed from the plasmid-encoded rrn operon. High-level resistance to many of the 4,6-disubstituted aminoglycosides is observed only when all the rRNA contains the U1406-to-A mutation. In contrast to the partial dominance of resistance observed with other mutations in the decoding region, there is a dominance of sensitivity with the 1406A mutation. Chemical footprinting experiments indicate that resistance arises from a reduced affinity of the antibiotic for the rRNA target. These results demonstrate that although position 1406 is an important determinant in the binding and action of the 4,6-disubstituted aminoglycosides, other rRNA mutations that perturb the binding of ring I of both classes of 2-deoxystreptamine aminoglycosides confer higher levels of resistance as well as a partial dominance of resistance.

Adenosine↗
PubMed1974

Active insolubilized antibiotics based on cellulose-metal chelates.

Cellulose was converted into a more reactive form by chelation with the transition metals titanium(III), iron(III), tin(IV), vanadium(III), and zirconium(IV). The remaining unsubstituted ligands of the transition metal ions were found to be amenable to replacement by electron-donating groups of antibiotic molecules. Ampicillin, gentamicin, kanamycin, neomycin, paromomycin, polymyxin B, and streptomycin were used as antibacterial antibiotics, and amphotericin B and natamycin were used as antifungal antibiotics. Antibacterial activity of the products was tested against two gram-positive and two gram-negative bacteria, and antifungal activity was tested against four fungi. That the antibacterial antibiotics had complexed with the cellulose-metal chelates was demonstrated in that the product cellulose-metal-antibiotic chelates exhibited antibiotic activities whereas the metal chelates of cellulose themselves were inactive. Of 140 tests conducted, cellulose-metal-antibiotic chelates were active in 102 cases. Since the antibiotic derivatives were water insoluble and in fact retain some of the antibacterial activities of the parent compounds, the chelation method provides a facile way of rendering cellulose surfaces, etc., resistant to microbial attack over and above that degree of protection afforded by noncovalent adsorption of the antibiotic to cellulose itself. The underlying principles of the chelation reactions involved are discussed in detail.

Anti-Bacterial Agents↗