Antibacterial activity of 2',3'-dideoxyadenosine in vivo and in vitro

Beskid, G.; Eskin, Barnet; Cleeland, Roy; Siebelist, J; Cappetta, A; Hill, A D; Geiger, Roger

doi:10.1128/aac.19.3.424

Cited by 17 publications

(7 citation statements)

References 15 publications

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“…In addition, it has been reported that the microbiotas in body sites other than the gut, such as the oral microbiota, are also changed under ART 19 , 20 . Furthermore, in vitro studies have indicated that an NRTI, zidovudine (AZT), exhibits antibacterial effects 21 likely due to inhibition of bacterial polymerases and/or induction of the SOS DNA damage response 22 – 25 . This evidence indicates that the gut microbiota of HIV-1-infected patients may be linked to gastrointestinal defects even under short-term ART.…”

Section: Introductionmentioning

confidence: 99%

Impact of long-term antiretroviral therapy on gut and oral microbiotas in HIV-1-infected patients

Imahashi

Ode

Kobayashi

et al. 2021

Sci Rep

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In HIV-1-infected patients, antiretroviral therapy (ART) is a key factor that may impact commensal microbiota and cause the emergence of side effects. However, it is not fully understood how long-term ART regimens have diverse impacts on the microbial compositions over time. Here, we performed 16S ribosomal RNA gene sequencing of the fecal and salivary microbiomes in patients under different long-term ART. We found that ART, especially conventional nucleotide/nucleoside reverse transcriptase inhibitor (NRTI)-based ART, has remarkable impacts on fecal microbial diversity: decreased α-diversity and increased ß-diversity over time. In contrast, dynamic diversity changes in the salivary microbiome were not observed. Comparative analysis of bacterial genus compositions showed a propensity for Prevotella-enriched and Bacteroides-poor gut microbiotas in patients with ART over time. In addition, we observed a gradual reduction in Bacteroides but drastic increases in Succinivibrio and/or Megasphaera under conventional ART. These results suggest that ART, especially NRTI-based ART, has more suppressive impacts on microbiota composition and diversity in the gut than in the mouth, which potentially causes intestinal dysbiosis in patients. Therefore, NRTI-sparing ART, especially integrase strand transfer inhibitor (INSTI)- and/or non-nucleotide reverse transcriptase inhibitor (NNRTI)-containing regimens, might alleviate the burden of intestinal dysbiosis in HIV-1-infected patients under long-term ART.

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Section: Introductionmentioning

confidence: 99%

Impact of long-term antiretroviral therapy on gut and oral microbiotas in HIV-1-infected patients

Imahashi

Ode

Kobayashi

et al. 2021

Sci Rep

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“…Second, metabolic inactivation of nucleosides such as ddA and ddC may occur because of deamination (7,8,30,39). Third, there appear to be differences in the abilities of microbial and mammalian DNA polymerases to incorporate dideoxynucleoside triphosphates into growing DNA chains (1,6,18,38); there also may be differences in the proofreading functions of various DNA polymerases or VOL. 34,1990 on May 12, 2018 by guest http://aac.asm.org/ Downloaded from in other processes associated with the removal or repair of incorporated dideoxynucleotides (18).…”

Section: Resultsmentioning

confidence: 99%

“…ddl, ddG, ddC, ddT, and D4T were inactive at 1,000 pg/ml. act as DNA chain terminators (1,6,13,38,39), it would be expected that they induce the SOS response. However, AZT and the dideoxynucleosides are structurally related to classical antimetabolites (18,37).…”

Section: Resultsmentioning

confidence: 99%

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Induction of the SOS response in Escherichia coli by azidothymidine and dideoxynucleosides

Mamber

Brookshire

Forenza

1990

Antimicrob Agents Chemother

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A number of nucleosides with anti-human immunodeficiency virus (HIV) activity were evaluated in two colorimetric (j-galactosidase) assays for induction of the SOS response in Escherichia coli. 3'-Azido-3'-deoxythymidine (azidothymidine; AZT), 2',3'-dideoxyadenosine (ddA), 2',3'-dideoxyguanosine (ddG), and 2',3'-dideoxyinosine (ddl) induced cel filamentation (sulA) and prophage lambda in well-agar diffusion and liquid microsuspension assays. AZT was approximately 100 times more potent than the dideoxypurine nucleosides, inducing sulA at <100 ng/ml. 2',3'-Dideoxythymidine (ddT) and 2',3'-dideoxy-2',3'-didehydrothymidine (D4T) induced sulA at 100 to 1,000 jg/ml, while 2',3'-dideoxycytidine (ddC) weakly induced prophage lambda. Activity relationships thus were AZT > ddA 2 ddl 2 ddG > ddT = D4T > ddC. ddA and ddl had equivalent activities in agar diffusion assays, but different activity profiles were observed in liquid microsuspension assays. The differences may be related to drug metabolism. AZT and ddA showed marginal effects in a DNA repair (preferential toxicity) assay in which E. coli WP2 and CM871 uvrA recA lexA were used. Furthermore, none of the agents was able to preferentially inhibit BaciUus subtilis M45 recA relative to wild-type strain H17. These data suggest that AZT and the dideoxynucleosides do not cause DNA lesions that are repairable by excision repair and/or error-free postreplication repair processes. Rather, the SOS response appears to be induced by DNA chain termination leading to the inhibition of DNA replication. Bacterial assays for induction of the SOS response may be useful as simple, rapid prescreens for the discovery of new anti-HIV agents. Moreover, such assays may provide an additional parameter in the evaluation of agents with demonstrated activity against HIV and other retroviruses.3'-Azido-3'-deoxythymidine (azidothymidine; AZT) and dideoxynucleosides such as 2',3'-dideoxyadenosine (ddA) and 2',3'-dideoxyinosine (ddI) have potential value in the chemotherapy of patients with acquired immunodeficiency syndrome (3,4,26,28,47). A proposed mechanism of action of these agents is the inhibition of human immunodeficiency virus (HIV) reverse transcriptase after nucleoside phosphorylation to their respective 5'-triphosphates (7,15,18,25,28,36,41). These agents have other biological activities, notably, an ability to terminate DNA chain elongation (1, 38, 39). DNA chain termination may play a role in the effects of these agents on HIV (2,4,14,26,27,36). Moreover, DNA chain termination is the mechanism postulated to explain the bactericidal effects of ddA and AZT against Escherichia coli and other members of the family Enterobacteriaceae (6,13). In 1972, Geissler et al. (16) reported that ddA induces prophage lambda in E. coli. Elwell et al. (13) noted that AZT causes filamentation of E. coli cells. These results suggest that AZT and the dideoxynucleosides are capable of inducing the SOS response (21, 34, 42-44), either by causing DNA damage or by inhibiting DNA replication. However, in the Sa...

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“…research aiming to repurpose existing nucleotide analog drugs that are commonly used in immunomediated conditions, neoplasia, or viral therapies identified multiple drug candidates with an in vitro antibacterial activity [16]. Early experiments on the antibacterial action of 2',3'-dideoxyadenosine (ddATP) were observed in vitro and in vivo for several bacteria [17,18]. Recent studies found the growth inhibition potential of purine analogs in multiple commensal and pathogenic gastrointestinal bacteria [19,20] caused by a disruption in the mechanisms of DNA replication or even inducing DNA break [21], but none of those studies included Corynebacterium species.…”

Section: Introductionmentioning

confidence: 99%

Potential in vitro action of an adenosine analog and synergism with penicillin against Corynebacterium pseudotuberculosis

et al. 2022

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Caseous lymphadenitis is a well-known disease caused by Corynebacterium pseudotuberculosis affecting small ruminants with small significance to human health because of its minor zoonotic potential. In both cases, few treatment options are available and conventional antimicrobial therapy is commonly refractory due to development of pyogranulomatous reactions, bringing great interest in discovering novel therapeutics for more suitable approaches. Dideoxynucleotides presented antibacterial action against various bacteria but were never described for C. pseudotuberculosis. Hypothesizing the antimicrobial action of 2',3'-dideoxiadenosine (ddATP) against C. pseudotuberculosis, we performed for the first time an investigation of its minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) in the ATCC® 19,410 strain and a well-characterized clinical isolate of C. pseudotuberculosis. We also assessed potential synergism with penicillin. ddATP showed a growth delay effect for C. pseudotuberculosis at 2 µmol/mL and a MIC and MBC of 4 µmol/mL against the ATCC® 19,410 strain, but not for the clinical strain. An antimicrobial effect was observed when using concentrations lower than the MIC of ddATP associated with penicillin for both strains tested. Our data suggest the potential of nucleotide analogs, especially adenosine, and its combination with penicillin, as a possible novel treatment for C. pseudotuberculosisinduced infections, and contributes with knowledge regarding alternative drugs to treat C. pseudotuberculosis infections.

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Antibacterial activity of 2',3'-dideoxyadenosine in vivo and in vitro

Cited by 17 publications

References 15 publications

Impact of long-term antiretroviral therapy on gut and oral microbiotas in HIV-1-infected patients

Impact of long-term antiretroviral therapy on gut and oral microbiotas in HIV-1-infected patients

Induction of the SOS response in Escherichia coli by azidothymidine and dideoxynucleosides

Potential in vitro action of an adenosine analog and synergism with penicillin against Corynebacterium pseudotuberculosis

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