Zidovudine-resistance in <i>Saimonella typhimurium</i> and <i>Escherichia coli</i>

Lewin, C. S.; Allen, Ruth A.; Amyes, Sebastian G. B.

doi:10.1093/jac/25.4.706

Cited by 18 publications

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“…44 Therefore, AZT also acts as an antibacterial agent, and previous studies have reported activity against Escherichia, Enterobacter, Klebsiella, Salmonella, and Shigella. [44][45][46][47] Our findings are therefore consistent with prior studies performed with a small number of carbapenem-susceptible Enterobacteriaceae strains. Notably, the antibiotics, trimethoprim and sulfamethoxazole, also interfere with DNA synthesis through modulation of the thymidine salvage pathway.…”

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confidence: 91%

Validation of a High-Throughput Screening Assay for Identification of Adjunctive and Directly Acting Antimicrobials Targeting Carbapenem-Resistant Enterobacteriaceae

Smith

Kirby

2016

ASSAY and Drug Development Technologies

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We describe development and validation of a high-throughput screen (HTS) for identifying small molecules that restore the efficacy of carbapenems (adjunctives) and/or directly inhibit growth of carbapenem-resistant Enterobacteriaceae (CRE). Our HTS assay is based on a screen-counterscreen approach using a representative multidrug-resistant CRE strain, Klebsiella pneumoniae BIDMC12A. Specifically, we tested the ability of small molecules to inhibit bacterial growth in the presence (screen) or absence (counterscreen) of meropenem, a representative carbapenem antibiotic. Primary screening of 11,698 known bioactive compounds identified 14 with adjunctive activity and 79 with direct antimicrobial effect. Secondary screening identified triclosan as a strongly synergistic meropenem adjunctive (fractional inhibitory concentration = 0.48) and confirmed azidothymidine (AZT) (minimal inhibitory concentration [MIC] = 4 lg mL ) as potent direct antimicrobials. Spectrum of activity of AZT and spectinomycin was tested against a collection of 103 representative Enterobacteriaceae strains (&50% CRE). AZT, a nucleoside analog used to treat human immunodeficiency virus, demonstrated an MIC 50 of 2 lg mL -1 . Spectinomycin, an antibiotic used to treat gonorrhea, had an MIC 50 of 32 lg mL -1 . Therefore, a significant percentage of CRE strains appeared relatively susceptible to these antimicrobials. These data identified AZT and spectinomycin as available agents warranting further study for potential treatment of multidrug-resistant CRE infection. Our results provide proof of principle and impetus for performing a largescale HTS for discovery of novel, small-molecule adjunctives and antibacterial agents directly targeting CRE.

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confidence: 91%

Validation of a High-Throughput Screening Assay for Identification of Adjunctive and Directly Acting Antimicrobials Targeting Carbapenem-Resistant Enterobacteriaceae

Smith

Kirby

2016

ASSAY and Drug Development Technologies

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“…13 Escherichia coli and Salmonella typhimurium develop stable high-level zidovudine resistance after short-term exposure to the drug in vitro at concentrations up to 100 MIC. 6 The mechanism of zidovudine resistance appears to involve the loss of thymidine kinase activity which is required to convert zidovudine to its active triphosphate This can be shown by the inability of thymidine to antagonise the action of trimethoprim in zidovudine-resistant mutants.6 Thymidine normally confers resistance to trimethoprim as the dihydrofolate reductase pathway can be bypa~sed,~ but this can happen only if the bacterium possesses thymidine kinase. This is only indirect evidence of thymidine kinase activity.…”

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confidence: 99%

Mechanisms of zidovudine resistance in bacteria

Lewin

Allen

Amyes

1990

Journal of Medical Microbiology

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Summary. Unlike their parent strains, zidovudine-resistant derivatives of Escherichia coli KL16 and Salmonella typhimurium NCTC 5710 were found to be incapable of incorporating radiolabelled thymidine into their chromosomal DNA. Since incorporation was still prevented in the presence of EDTA, resistance to zidovudine was not associated with a permeability barrier, but appeared to result from the loss of thymidine kinase activity, required for the phosphorylation of zidovudine. Pseudomonas aeruginosa, which is intrinsically zidovudine-resistant, was also shown to be incapable of incorporating thymidine into its DNA, but Staphylococcus epidermidis SK360 and Staph. aureus E3T, which are also intrinsically zidovudine-resistant, possessed thymidine kinase activity. This suggests that two distinct mechanisms of resistance to zidovudine exist in bacteria. Zidovudine resistance did not appear to confer resistance to other antibacterial agents.

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“…The absence of thymidine kinase activity is observed with P. aeruginosa and Listeria species that are naturally resistant to AZT. However, this resistance is not transferable (9,10).…”

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confidence: 99%

Intracellular activity of zidovudine (3'-azido-3'-deoxythymidine, AZT) against Salmonella typhimurium in the macrophage cell line J774-2

Herrmann

1992

Antimicrob Agents Chemother

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The antibacterial effect of zidovudine (AZT) has been demonstrated both in vitro and in vivo with experimental models of gram-negative bacterial infections. It has been associated with the absence or low occurrence of nontyphoid SalmoneUla infections in AIDS patients treated with AZT. Using the macrophage cell line J774-2, we demonstrate the inhibition of intracellular growth of Salmonella typhimurium by AZT. This effect is obtained with one-half of the MIC (1 ,ug/ml) of AZT for S. typhimurium. Inhibition of intracellular growth is observed after 4 h of incubation and persists at 24 h. Maximal inhibition is shown at a concentration of 128 ,ug/ml, and no further effect is observed with higher concentrations. When the inhibitory effect of AZT is compared with that of pefloxacin or that of ceftriaxone at half their MICs (0.2 and 0.02 ,ug/ml, respectively), AZT and pefloxacin give better results than ceftriaxone. In this study, using an intracellular model, we show that AZT is able to inhibit the intracellular multiplication of S. typhimurium at a minimal effective concentration lower than the MIC, indicating its potential for antibacterial accumulation in the macrophages.

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Zidovudine-resistance in Saimonella typhimurium and Escherichia coli

Cited by 18 publications

References 0 publications

Validation of a High-Throughput Screening Assay for Identification of Adjunctive and Directly Acting Antimicrobials Targeting Carbapenem-Resistant Enterobacteriaceae

Validation of a High-Throughput Screening Assay for Identification of Adjunctive and Directly Acting Antimicrobials Targeting Carbapenem-Resistant Enterobacteriaceae

Mechanisms of zidovudine resistance in bacteria

Intracellular activity of zidovudine (3'-azido-3'-deoxythymidine, AZT) against Salmonella typhimurium in the macrophage cell line J774-2

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