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PubMed1978

Inhibition by paromomycin of R-factor transfer of tetracycline resistance between Escherichia coli and Salmonella pullorum.

In vitro assays showed that low concentrations (5--10 and 20 microgram/ml) of the antimicrobial paromomycin sulfate are able to block or diminish significantly the transfer of the tetracycline resistance R-factor between Escherichia coli and Salmonella pullorum. This observation is important because it offers the possibility of preventing the formation of tetracycline-resistant pathogens, a limiting factor of tetracycline use in both human and veterinary medicine.

Coliphages↗
PubMed1993

Leishmania major: respiratory burst response of infected murine macrophages treated with paromomycin.

The effect of paromomycin sulfate (PR) on the respiratory burst response (RB) of C3H/HeJ mouse peritoneal macrophages infected with Leishmania major, LRC-L137, was studied in vitro. Giemsa staining and acridine orange staining combined with nitro blue tetrazolium (NBT) reduction reaction were used to determine parasite survival and RB response at the level of individual cells. RB response was detected in only 18% of the infected macrophages compared with 60% of the control, uninfected cells. Only 7% of the total RB-responder (NBT-positive) cells showed the presence of intracellular amastigotes. PR at 100 micrograms/ml reduced the number of the infected cells by 85% on the 4th day of cultivation. PR at the same concentration restored 50% of the RB activity of these cells. PR given alone had no effect on the RB of the uninfected macrophages. A similar effect of PR on RB activity was observed with PMA-stimulated macrophages. Both Leishmania-infected and uninfected macrophages treated with PR (100 micrograms/ml) for 4 days retained 50% of their leishmanicidal activity upon reinfection due to drug accumulation within the cells.

Animals↗
PubMed1979

Suppression of mitochondrially-determined resistance to chloramphenicol and paromomycin by nuclear genes in Saccharomyces cerevisiae.

Phenotypic "revertants" of a drug resistant strain of Saccharomyces cerevisiae were induced by mutgenesis with manganese. Several of these drug sensitive mutants have been shown to result from mutations in the nuclear genome that cause phenotypic modification (suppression) of the mitochondrially-determined drug resistant genotype. Four mutants carrying a single recessive nuclear gene capable of modifying mitochondrial chloramphenicol resistance are described; these may be assigned to three complementation groups. Chloramphenicol resistant mutants mapping at five separate mitochondrial loci are described. At least two of the nuclear genes cause modification of mitochondrial chloramphenicol resistance determined by mutations at three of these loci, but the other two loci are apparently non-suppressible by these nuclear alleles. This indicates that these modifiers do not act by causing a general decrease in cellular or mitochondrial permeability to the drug. A single dominant nuclear modifier of mitochondrial paromomycin resistance has been identified. It is non-allelic to and does not interact with the genes modifying mitochondrial chloramphenicol resistance.

Chloramphenicol↗
PubMed1986

Inherent resistance of HeLa cell derivatives to paromomycin.

The human tumor-derived cell line HeLa S3 and nuclear and mitochondrial gene mutants derived from it are resistant to the aminoglycoside antibiotic, paromomycin (PAR). Other carcinoma-derived cells, SV40-transformed cells, and four human diploid fibroblast cell lines are all sensitive to PAR. Sensitivity is dependent on cell density, and at cell numbers greater than 400/cm2 sensitive cells will proliferate in PAR. The resistance to PAR is inherited in a dominant manner in cell-to-cell fusion hybrids, but is not transferred in cytoplast-to-cell fusions. PAR resistance is therefore encoded by a nuclear gene(s). Resistance to PAR is not caused by changes in the response of mitochondrial or cytoplasmic protein synthesis to PAR in vitro. The uptake of PAR is similar in resistant and sensitive cells, and dimethyl sulfoxide does not render resistant cells more sensitive. Thus, HeLa cell PAR resistance is unlike previously reported ribosomal mutations and may derive from differences in the intracellular metabolism of PAR.

Adrenal Cortex Neoplasms↗
PubMed2003

Neomycin and paromomycin inhibit 30S ribosomal subunit assembly in Staphylococcus aureus.

A number of different antibiotics that prevent translation by binding to the 50S ribosomal subunit of bacterial cells have recently been shown to also prevent assembly of this subunit. Antibacterial agents affecting 30S particle activities have not been examined extensively for effects on small subunit formation. The aminoglycoside antibiotics paromomycin and neomycin bind specifically to the 30S ribosomal subunit and inhibit translation. These drugs were examined in Staphylococcus aureus cells to see whether they had a second inhibitory effect on 30S particle assembly. A 3H-uridine pulse and chase assay was used to examine the kinetics of subunit synthesis in the presence and absence of each antibiotic. 30S subunit formation was inhibited by both compounds. At 3 microg/mL each antibiotic reduced the rate of 30S formation by 80% compared with control cells. Both antibiotics showed a concentration-dependent inhibition of particle formation, with a lesser effect on 50S particle formation. For neomycin, the IC50 for 30S particle formation was equal to the IC50 for inhibition of translation. Both antibiotics reduced the viable cell number with an IC50 of 2 microg/mL. They also inhibited protein synthesis in the cells with different IC50 values (2.5 and 1.25 microg/mL). This is the second demonstration of 30S ribosomal subunit-specific antibiotics that prevent assembly of the small subunit.

Anti-Bacterial Agents↗
PubMed2006

Cryptosporidium parvum bovine genotype oocysts in the respiratory samples of an AIDS patient: efficacy of treatment with a combination of azithromycin and paromomycin.

Cryptosporidium has been recognized as an emerging zoonotic agent of intestinal cryptosporidiosis leading to diarrhea, malabsorption syndrome, and weight loss in AIDS patients. In the present case, oocysts of zoonotic Cryptosporidium parvum were detected in the sputum and stool samples of an AIDS patient with a 3-month history of intestinal cryptosporidiosis. The oocysts were detected by modified Ziehl-Neelsen staining; confirmation was achieved by nested polymerase chain reaction (PCR), targeting the most polymorphic region of the 18S rRNA gene. Genotyping was done by restriction endonuclease digestion of the PCR product. The zoonotic C. parvum bovine genotype was identified in both intestinal and respiratory samples. Treatment with both azithromycin and paromomycin resulted in improvement of both intestinal and respiratory symptoms, as well as the elimination of the parasite. This is the first report of the identification of Cryptosporidium sp. oocysts in the respiratory samples obtained from an AIDS patient in Iran. Pulmonary cryptosporidiosis should be considered whenever an AIDS patient with intestinal cryptosporidiosis develops respiratory symptoms.

AIDS-Related Opportunistic Infections↗
PubMed1997

Biochemical alterations in paromomycin-treated Leishmania donovani promastigotes.

Paromomycin is used for the treatment of leishmaniasis in humans, but little is known about its mechanism of action. Investigating the effect of this antibiotic on promastigotes of Leishmania donovani, we showed that inhibition of the multiplication of these parasites could be related to its effect on RNA synthesis and to modifications of membranous polar lipids and membrane fluidity, leading to altered membrane permeability.

Amebicides↗
PubMed1983

Leishmania tropica major: effect of paromomycin and pentamidine on polyamine levels in the skin of normal and infected mice.

The polyamine content of the skin of BALB/c and C3H mice was determined at intervals, after injecting Leishmania tropica major. In BALB/c mice, putrescine and spermidine levels increased three- to seven-fold; in C3H mice, spontaneous recovery occurred after 3 weeks, accompanied by a reduction in putrescine and spermidine levels. Ornithine decarboxylase activity was negligible in normal, uninfected skin of both BALB/c and C3H mice, but increased steadily during infection. Treatment with drugs that inhibit the growth of leishmanial amastigotes in the skin of mice also reduced polyamine levels and ornithine decarboxylase activity of previously infected skin. There was a close correlation between the therapeutic activity of the drugs and their effect on polyamine content and synthesis. The aminoglycoside paromomycin, which was chemotherapeutically more effective than pentamidine, also had a greater effect on polyamine levels. S-adenosyl-L-Methionine decarboxylase activity in the skin of BALB/c and C3H mice was only slightly affected by the parasites. Polyamine levels and ornithine decarboxylase activity could possibly serve as means for measuring the growth of leishmanial parasites in skin and other tissues and as a measure of the efficacy of anti-leishmanial chemotherapeutics.

Adenosylmethionine Decarboxylase↗
PubMedDate not supplied

Treatment of visceral leishmaniasis (kala-azar) with aminosidine (= paromomycin)-antimonial combinations, a pilot study in Bihar, India.

A 20 d drug regimen of aminosidine (= paromomycin) at 12 mg/kg/d in combination with sodium stibogluconate at 20 mg/kg/d proved efficacious and well-tolerated in patients with visceral leishmaniasis in the State of Bihar, India. Eighteen of 22 evaluable patients achieved an ultimate cure. The remaining 4 patients, although not cleared of parasites, had their parasite grade reduced and also improved clinically. This confirms prior findings in Kenyan patients with kala-azar, and indicates that this regimen is a valid alternative to antimonial compounds alone in the State of Bihar, where cases of kala-azar not responding to antimonial drugs and intolerant of pentamidine are increasingly recorded.

Adolescent↗
PubMed1995

Consequences of the overexpression of ubiquitin in yeast: elevated tolerances of osmostress, ethanol and canavanine, yet reduced tolerances of cadmium, arsenite and paromomycin.

Ubiquitin is induced by diverse stresses in all eukaroytes probably in reflection of the need for more extensive protein turnover by the ubiquitination system in stressed cells. To determine if ubiquitin overexpression can confer general protection against different stresses, yeast cells were engineered to overexpress ubiquitin and the effects of this overexpression on different stress tolerances determined. Ethanol and osmostress tolerances were slightly increased by ubiquitin overexpression, tolerance to heat was unaffected, while still other tolerances were reduced as compared to cells with normal ubiquitin levels. It is noteworthy that tolerance of the amino acid analogue canavanine was markedly increased by ubiquitin overexpression, yet resistance to at least three other agents that contribute to accumulation of aberrant proteins (arsenite, cadmium, paromomycin) was decreased.

Arsenites↗
PubMed1991

Interaction between 16S ribosomal RNA and ribosomal protein S12: differential effects of paromomycin and streptomycin.

Strains containing a series of restrictive and non-restrictive mutations in ribosomal protein S12 have been transformed with plasmids carrying the rrnB operon with mutations at positions 1409 and 1491 in 16S rRNA. The effects of the double-mutant constructs have been measured by growth rate, paromomycin and streptomycin sensitivity, resistance and dependence. The results demonstrate a functional interaction between the 1409-1491 region of rRNA and ribosomal protein S12.

Bacterial Proteins↗
PubMed1987

Altered sensitivity of protein synthesis to paromomycin in extracts from aging human diploid fibroblasts.

Age-related differences in the effects of paromomycin (Pm) on protein synthesis have been investigated in translation reactions with extracts derived from young and old human diploid fibroblasts. Translation products from reactions directed by endogenous or exogenous mRNA were analyzed by polyacrylamide gel electrophoresis and fluorography. The exogenous mRNA lacked codons for cysteine, and therefore cysteine incorporation into translation products represented translational error. This laboratory has previously used this assay to show that the basal translational error level in the absence of Pm increases in extracts from old fibroblasts. In this report, Pm stimulated the misincorporation of cysteine by 6-7 fold over cysteine misincorporation levels in the absence of Pm. This degree of Pm stimulation was similar in extracts from young and old fibroblasts. However, other results showed quantitative differences in the responses to Pm between young and old cell extracts. Old cell extracts were less sensitive to the stimulation of the rate of protein synthesis, and more sensitive to the inhibition of protein synthesis, by Pm. It is proposed that aging human diploid fibroblasts contain altered ribosomes which react differently with Pm.

Aging↗
PubMed2004

Activity of a paromomycin hydrophilic formulation for topical treatment of infections by Leishmania (Leishmania) amazonensis and Leishmania (Viannia) braziliensis.

Studies on in vitro skin permeation and in vivo anti-leishmanial activity in mice experimentally infected with Leishmania (Leishmania) major pointed out to the potential of a new paromomycin (PA) formulation (hydrophilic gel) for treatment of cutaneous leishmaniasis (CL). In this study, the activity of this formulation was evaluated in animals experimentally infected by Leishmania species that prevail in the New World. PA gel activity was compared to antimony treatment, since it is still the first choice treatment to the different clinical forms of leishmaniasis. The topical treatment activity with 10% PA gel in BALB/c mice infected by Leishmania (Leishmania) amazonensis was higher than that observed for parenteral antimony treatment, while the efficacy of these two regimes in hamsters infected by Leishmania (Viannia) braziliensis was similar. These results suggest that this formulation could be suitable for clinical studies and may represent an alternative novel formulation for topical treatment of CL.

Administration, Topical↗
PubMed2005

Linear indices of the 'macromolecular graph's nucleotides adjacency matrix' as a promising approach for bioinformatics studies. Part 1: prediction of paromomycin's affinity constant with HIV-1 psi-RNA packaging region.

The design of novel anti-HIV compounds has now become a crucial area for scientists around the world. In this paper a new set of macromolecular descriptors (that are calculated from the macromolecular graph's nucleotide adjacency matrix) of relevance to nucleic acid QSAR/QSPR studies, nucleic acids' linear indices. A study of the interaction of the antibiotic Paromomycin with the packaging region of the HIV-1 psi-RNA has been performed as example of this approach. A multiple linear regression model predicted the local binding affinity constants [Log K (10(-4) M(-1))] between a specific nucleotide and the aforementioned antibiotic. The linear model explains more than 87% of the variance of the experimental Log K (R = 0.93 and s = 0.102 x 10(-4) M(-1)) and leave-one-out press statistics evidenced its predictive ability (q2 = 0.82 and s(cv) = 0.108 x 10(-4) M(-1)). The comparison with other approaches (macromolecular quadratic indices, Markovian Negentropies and 'stochastic' spectral moments) reveals a good behavior of our method.

Anti-Bacterial Agents↗
PubMedDate not supplied

A prospective randomized, comparative, open-label trial of the safety and efficacy of paromomycin (aminosidine) plus sodium stibogluconate versus sodium stibogluconate alone for the treatment of visceral leishmaniasis.

Response to treatment with organic pentavalent antimonials, the standard first-line treatment for visceral leishmaniasis (VL), has been decreasing since their introduction into India. Combining sodium stibogluconate (SB) with paromomycin (PM) may be an efficient alternative to single-agent therapy. This trial was designed to assess the safety and efficacy of PM 12 or 18 mg/kg daily plus SB 20 mg/kg daily for 21 days compared to SB alone for 30 days. One hundred and fifty patients were randomly assigned in 1996 to 1 of the 3 treatments and followed-up for 180 days. At the end of treatment, 49 of 52 patients receiving PM12 + SB, 46 of 48 receiving PM18 + SB, and 27 of 49 patients receiving SB alone, were cured. During follow-up there was 1 relapse in each of the treatment groups, giving final cure rates of 48 of 52 (92.3%) for PM12 + SB, 45 of 48 (93.8%) for PM18 + SB, and 26 of 49 (53.1%) for SB. PM plus SB for 21 days at either 12 or 18 mg/kg daily was significantly more effective than SB alone for 30 days (chi 2 P < 0.001). One patient (SB alone) had experienced a serious adverse event: cardiotoxicity at day 8 (myocarditis and ECG changes) which caused withdrawal from the study. Only 19 of 100 patients enrolled in the PM treatment arms had a complete audiogram series conducted thus making it difficult to assess oto-toxicity. PM 12 or 18 mg/kg daily plus a standard dose of SB for 21 days was statistically more effective than SB in producing a final cure for patients with VL in Bihar, India.

Adolescent↗
PubMedDate not supplied

Non-ulcerative cutaneous leishmaniasis in Honduras fails to respond to topical paromomycin.

A double-'blind', placebo-controlled trial of topical therapy with 15% paromomycin (aminosidine) and 10% urea in white paraffin was carried out on 53 patients with non-ulcerating cutaneous leishmaniasis in Honduras. Although the treatment was not effective, several unexpected findings emerged from the trial. Leishmania mexicana was found to be the cause of many of the skin lesions in one of the 2 study sites. These lesions were clinically indistinguishable from those caused by L. chagasi, the aetiologic agent previously found for this form of leishmaniasis. This is the first documented report of L. mexicana in Honduras.

Administration, Topical↗
PubMed2003

Structure-activity relationship of neomycin, paromomycin, and neamine-arginine conjugates, targeting HIV-1 gp120-CXCR4 binding step.

We have recently designed and synthesized aminoglycoside-arginine conjugates (AACs) as potential anti-HIV-1 agents. AACs exert a number of activities related to Tat antagonism. We here present a new set of AACs, conjugates of neomycin B, paromomycin, and neamine with different number of arginines (1-6), their (a) uptake by human T-cell lines, (b) antiviral activities, (c) competition with monoclonal antibody (mAb) 12G5 binding to CXCR4, (d) competition with stromal cell-derived factor-1 (SDF-1alpha) binding to CXCR4, and (e) competition with HIV-1 coat protein gp120 cell penetration. The appearance of mutations in HIV-1 gp120 gene in AACs resistant HIV-1 isolates, supports that AACs inhibit HIV-1 infectivity via interference of gp120-CXCR4 interaction. Our results point that the most potent AACs is the hexa-arginine-neomycin conjugate, the other multi-arginine-aminoglycoside conjugates are less active, and the mono-arginine conjugates display the lowest activity. Our studies demonstrate that, in addition to the core, the number of arginines attached to a specific aminoglycoside, are also important in the design of potent anti-HIV agents. The AACs play an important role, not only as HIV-1 RNA binders but also as inhibitors of viral entry into human cells.

Anti-HIV Agents↗
PubMed1996

Mutations in yeast ribosomal proteins S28 and S4 affect the accuracy of translation and alter the sensitivity of the ribosomes to paromomycin.

Ribosomal proteins S12, S5 and S4 of Escherichia coli are essential for the control of translational accuracy. Their yeast equivalents, i.e., S28, S4 and S13, have also been implicated in this process. Using a poly(U)-dependent cell-free translation system, we determined the accuracy of translation and the sensitivity to antibiotic paromomycin of yeast ribosomes carrying mutant ribosomal proteins S28 and/or S4. Our results confirm by quantitative biochemical methods previous genetic data showing that proteins S28 and S4 are involved in the decoding activity of the ribosome and interact to control translational accuracy. We find that the suppressor mutation SUP44 in yeast S4, decreased the accuracy of translation. To examine the effect of mutant S28, we disrupted RPS28B and introduced in RPS28A the same substitutions that cause hyperaccurate translation or antibiotic resistance in bacteria. Three of these substitutions (Lys-62-->Asn, Thr or Gln) similarly increased translational accuracy in vitro or antibiotic resistance. In the presence of the SUP44 mutation, these substitutions partially reversed the decrease of translational accuracy caused by SUP44. However, the Lys-62-->Arg substitution decreased translational accuracy and caused antibiotic sensitivity both in nonsuppressor and in SUP44 haploids. These results establish the role of Lys-62 of S28 in optimizing translational accuracy and provide a more precise view of the functional role of two important ribosomal proteins.

Anti-Bacterial Agents↗