Effect of Fluoropyrimidines on the Growth of<i>Ureaplasma urealyticum</i>

Wehelie, Rahma; Eriksson, Staffan; Wang, Liya

doi:10.1081/ncn-200027714

Cited by 10 publications

(4 citation statements)

References 3 publications

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“…Halogenated pyrimidine analogs such as 5FdU inhibited Mpn and Ureaplasma growth, as reported in our earlier studies [30,35]. Others have shown that TFT and 5FdU inhibited Cryptosporidium growth [47], and gemcitabine inhibited Staphylococcus aureus growth in vitro and in animal models [48].…”

Section: Discussionsupporting

confidence: 78%

“…Some nucleoside analogs have been reported to inhibit Mycoplasma growth [30,35]. Recently a nucleoside and nucleobase analog library consisting of FDA-approved prodrugs used in anticancer and antiviral therapy was used to screen human enzymes in nucleotide metabolism, and new interactions were found [36], which promoted the use of these analogs in screening for inhibitory effects on Mpn growth.…”

Section: Resultsmentioning

confidence: 99%

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Inhibition of Mycoplasma pneumoniae growth by FDA-approved anticancer and antiviral nucleoside and nucleobase analogs

Sun

Wang

2013

BMC Microbiol

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BackgroundMycoplasma pneumoniae (Mpn) is a human pathogen that causes acute and chronic respiratory diseases and has been linked to many extrapulmonary diseases. Due to the lack of cell wall, Mpn is resistant to antibiotics targeting cell wall synthesis such as penicillin. During the last 10 years macrolide-resistant Mpn strains have been frequently reported in Asian countries and have been spreading to Europe and the United States. Therefore, new antibiotics are needed. In this study, 30 FDA-approved anticancer or antiviral drugs were screened for inhibitory effects on Mpn growth and selected analogs were further characterized by inhibition of target enzymes and metabolism of radiolabeled substrates.ResultsSixteen drugs showed varying inhibitory effects and seven showed strong inhibition of Mpn growth. The anticancer drug 6-thioguanine had a MIC (minimum inhibitory concentration required to cause 90% of growth inhibition) value of 0.20 μg ml-1, whereas trifluorothymidine, gemcitabine and dipyridamole had MIC values of approximately 2 μg ml-1. In wild type Mpn culture the presence of 6-thioguanine and dipyridamole strongly inhibited the uptake and metabolism of hypoxanthine and guanine while gemcitabine inhibited the uptake and metabolism of all nucleobases and thymidine. Trifluorothymidine and 5-fluorodeoxyuridine, however, stimulated the uptake and incorporation of radiolabeled thymidine and this stimulation was due to induction of thymidine kinase activity. Furthermore, Mpn hypoxanthine guanine phosphoribosyl transferase (HPRT) was cloned, expressed, and characterized. The 6-thioguanine, but not other purine analogs, strongly inhibited HPRT, which may in part explain the observed growth inhibition. Trifluorothymidine and 5-fluorodeoxyuridine were shown to be good substrates and inhibitors for thymidine kinase from human and Mycoplasma sources.ConclusionWe have shown that several anticancer and antiviral nucleoside and nucleobase analogs are potent inhibitors of Mpn growth and that the mechanism of inhibition are most likely due to inhibition of enzymes in the nucleotide biosynthesis pathway and nucleoside transporter. Our results suggest that enzymes in Mycoplasma nucleotide biosynthesis are potential targets for future design of antibiotics against Mycoplasma infection.

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Section: Discussionsupporting

confidence: 78%

Section: Resultsmentioning

confidence: 99%

Inhibition of Mycoplasma pneumoniae growth by FDA-approved anticancer and antiviral nucleoside and nucleobase analogs

Sun

Wang

2013

BMC Microbiol

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“…Various fluorinated pyrimidines could inhibit the growth of the human pathogen Ureaplasma urealyticum (Carnrot et al, 2003). Floxuridine had a strong effect in vitro, inhibiting the growth of U. urealyticum for up to 72 h. This finding was supported by a later study (Wehelie et al, 2004). Subsequently, various Gram-positive and Gram-negative bacteria were found to be susceptible to floxuridine (Sandrini et al, 2007a,b;Zander et al, 2010a).…”

Section: Fluorinated Pyrimidinesmentioning

confidence: 89%

Nucleoside Analogues as Antibacterial Agents

2019

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The rapid increase in antibiotic-resistant bacteria has emphasized the urgent need to identify new treatments for bacterial infections. One attractive approach, reducing the need for expensive and time-consuming clinical trials, is to repurpose existing clinically approved compounds for use as antibacterial agents. Nucleoside analogues are commonly used for treating viral and fungal infections, as well as for treating cancers, but have received relatively little attention as treatments for bacterial infections. However, a significant number of clinically approved derivatives of both pyrimidines and purines including halogenated, thiolated, and azolated compounds have been shown to have antibacterial activity. In the small number of studies carried out to date, such compounds have shown promise in treating bacterial infections. Here, we review the mechanisms of action and antibacterial activities of nucleoside analogues that can potentially be repurposed for treating infections as well as considering possible limitations in their usage.

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“…Troemel et al added 5-fluorodeoxyuridine (FUDR) to NGM plates seeded with OP50, to prevent C. elegans progeny. However, FUDR acts to inhibit DNA synthesis, and also inhibits bacterial proliferation [76]. That abrogating two host anti-bacterial mechanisms (e.g.…”

Section: Discussionmentioning

confidence: 99%

Control of intestinal bacterial proliferation in regulation of lifespan in Caenorhabditis elegans

2012

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BackgroundA powerful approach to understanding complex processes such as aging is to use model organisms amenable to genetic manipulation, and to seek relevant phenotypes to measure. Caenorhabditis elegans is particularly suited to studies of aging, since numerous single-gene mutations have been identified that affect its lifespan; it possesses an innate immune system employing evolutionarily conserved signaling pathways affecting longevity. As worms age, bacteria accumulate in the intestinal tract. However, quantitative relationships between worm genotype, lifespan, and intestinal lumen bacterial load have not been examined. We hypothesized that gut immunity is less efficient in older animals, leading to enhanced bacterial accumulation, reducing longevity. To address this question, we evaluated the ability of worms to control bacterial accumulation as a functional marker of intestinal immunity.ResultsWe show that as adult worms age, several C. elegans genotypes show diminished capacity to control intestinal bacterial accumulation. We provide evidence that intestinal bacterial load, regulated by gut immunity, is an important causative factor of lifespan determination; the effects are specified by bacterial strain, worm genotype, and biologic age, all acting in concert.ConclusionsIn total, these studies focus attention on the worm intestine as a locus that influences longevity in the presence of an accumulating bacterial population. Further studies defining the interplay between bacterial species and host immunity in C. elegans may provide insights into the general mechanisms of aging and age-related diseases.

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Effect of Fluoropyrimidines on the Growth ofUreaplasma urealyticum

Cited by 10 publications

References 3 publications

Inhibition of Mycoplasma pneumoniae growth by FDA-approved anticancer and antiviral nucleoside and nucleobase analogs

Inhibition of Mycoplasma pneumoniae growth by FDA-approved anticancer and antiviral nucleoside and nucleobase analogs

Nucleoside Analogues as Antibacterial Agents

Control of intestinal bacterial proliferation in regulation of lifespan in Caenorhabditis elegans

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