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Background: The viral RNA-dependent RNA polymerase (RdRp) enzymes of the Flaviviridae family are essential for viral replication and are logically important targets for development of antiviral therapeutic agents. Zika virus (ZIKV) is a rapidly re-emerging human pathogen for which no vaccine or antiviral agent is currently available.Methods: To facilitate development of ZIKV RdRp inhibitors, we have established an RdRp assay using purified recombinant ZIKV NS5 polymerase.Results: We have shown that both the hepatitis C virus (HCV) nucleoside inhibitor sofosbuvir triphosphate and a pyridoxine-derived non-nucleoside small-molecule inhibitor, DMB213, can act against ZIKV RdRp activity at IC 50 s of 7.3 and 5.2 μM, respectively, in RNA synthesis reactions catalysed by recombinant ZIKV NS5 polymerase. Cell-based assays confirmed the anti-ZIKV activity of sofosbuvir and DMB213 with 50% effective concentrations (EC 50 s) of 8.3 and 4.6 μM, respectively. Control studies showed that DMB213 did not inhibit recombinant HIV-1 reverse transcriptase and showed only very weak inhibition of HIV-1 integrase strand-transfer activity. The S604T substitution in motif B of the ZIKV RdRp, which corresponds to the S282T substitution in motif B of HCV RdRp, which confers resistance to nucleotide inhibitors, also conferred resistance to sofosbuvir triphosphate, but not to DMB213. Enzyme assays showed that DMB213 appears to be competitive with natural nucleoside triphosphate (NTP) substrates.Conclusions: Recombinant ZIKV RdRp assays can be useful tools for the screening of both nucleos(t)ide compounds and non-nucleotide metal ion-chelating agents that interfere with ZIKV replication. [ABSTRACT FROM AUTHOR]

Background: Current guidelines recommend adjunctive gentamicin for the treatment of Enterococcus faecalis infective endocarditis (EFIE) despite a risk of toxicity. We sought to revisit the evidence for adjunctive therapy in EFIE and to synthesize the comparative safety and effectiveness of adjunctive use of the aminoglycosides versus ceftriaxone by systematic review and meta-analysis., Methods: For historical context, we reviewed the seminal case series and in vitro studies informing the evolution from penicillin monotherapy to modern-day regimens for EFIE. Next, we searched MEDLINE and Embase from inception to January 16, 2024 for studies of EFIE comparing 1) adjunctive aminoglycosides versus ceftriaxone or 2) adjunctive therapy versus monotherapy. Where possible, clinical outcomes were compared between regimens by random-effects meta-analysis. Otherwise, data were narratively summarized., Results: Results for the systematic review and meta-analysis were limited to 10 observational studies totaling 911 patients. All studies were at high risk of bias. Relative to adjunctive ceftriaxone, gentamicin had similar all-cause mortality (Risk Difference [RD]=-0.8%, 95% Confidence interval [95%CI]=-5.0, 3.5), relapse (RD=-0.1%, 95%CI=-2.4, 2.3), and treatment failure (RD=1.1%, 95%CI=-1.6, 3.7), but higher discontinuation due to toxicity (RD=26.3%, 95%CI=19.8, 32.7). The 3 studies comparing adjunctive therapy to monotherapy included only 30 monotherapy patients and heterogeneity precluded meta-analysis., Conclusion: Adjunctive therapy with ceftriaxone appeared to be equally effective and less toxic than gentamicin for the treatment of EFIE. The existing evidence does not clearly establish the superiority of either adjunctive therapy or monotherapy. Pending randomized evidence, if adjunctive therapy is to be used, ceftriaxone appears to be a reasonable option., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)