Bacterial resistance to antimicrobial agents has become an increasingly serious health problem in recent years. Among the strategies by which resistance can be achieved, overexpression of efflux pumps such as NorA of Staphylococcus aureus leads to a sub‐lethal concentration of the antibacterial agent at the active site that in turn may predispose the organism to the development of high‐level target‐based resistance. With an aim to improve both the chemical stability and potency of our previously reported 3‐phenyl‐1,4‐benzothiazine NorA inhibitors, we replaced the benzothiazine core with different nuclei. None of the new synthesized compounds showed any appreciable intrinsic antibacterial activity, and, in particular, 2‐(3,4‐dimethoxyphenyl)quinoline (6 c) was able to decrease, in a concentration‐dependent manner, the ciprofloxacin MIC against the norA‐overexpressing strains S. aureus SA‐K2378 (norA++) and SA‐1199B (norA+/A116E GrlA).

Treatment of dengue virus (DENV) and other flavivirus infections is an unmet medical need. The highly conserved flaviviral NS5 RNA-dependent RNA polymerase (RdRp) is an attractive antiviral target that interacts with NS3 and viral RNA within the replication complex assembly. Biochemical and cell-based evidence indicate that targeting cavity B may lead to dual RdRp and NS5–NS3 interaction inhibitors. By ligand-based design around 1H-pyrido­[2,1-b]­[1,3]­benzothiazol-1-one (PBTZ) 1, we identified new potent and selective DENV inhibitors that exert dual inhibition of NS5 RdRp and NS3–NS5 interaction, likely through binding cavity B. Resistance studies with compound 4 generated sequence variants in the 3′-untranslated region of RNA while further biochemical experiments demonstrated its ability to block also RNA-NS5 interaction, required for correct RNA synthesis in cells. These findings shed light on the potential mechanism of action for this class of compounds, underlying how PBTZs are very promising lead candidates for further evaluation.

Surveillance of Usutu virus is crucial to prevent future outbreaks both in Europe and in other countries currently naïve to the infection, such as the Americas. This goal remains difficult to achieve, notably because of the lack of large-scale cohort studies and the absence of commercially available diagnostic reagents for USUV. This work started with the first identification of USUV in a blood donor in the Friuli Venezia Giulia (FVG) Region in Northern-Eastern Italy, which is endemic for West Nile virus. Considering that only one IgG ELISA is commercially available, but none for IgM, a novel NS1 antigen based IgG/M ELISA has been developed. This assay tested successfully for the detection of Usutu virus in blood donors with the identification of a second case of transmission and high levels of exposure. Furthermore, two pan-flavivirus antiviral drugs, that we previously characterized to be inhibitors of other flavivirus infectivity, were successfully tested for inhibition of Usutu virus with inhibitory concentrations in the low micromolar range. To conclude, this work identifies NorthEastern Italy as endemic for Usutu virus with implications for the screening of transfusion blood. A novel NS1-based ELISA test has been implemented for the detection of IgM/G that will be of importance as a tool for the diagnosis and surveillance of Usutu virus infection. Finally, Usutu virus is shown to be sensitive to a class of promising pan-flavivirus drugs.

The front cover picture shows the everlasting fight between bacteria and humans. Bacteria, which have lost their susceptibility to antimicrobials, are able to survive in the host like Trojan warriors, resisting almost all our weapons. In this bloody war, efflux pump overexpression plays a key role in conferring resistance to a variety of antibacterials. Compounds able to inhibit such pumps (e.g., efflux pump inhibitors or EPIs) act as Trojan horses thus giving new life to old antibacterial agents. Indeed, EPIs should both allow the antibacterials to reach their intracellular target, hence killing the pathogen, and simultaneously be devoid of any antibacterial activity so as not to induce further resistance phenomena. More information can be found in the Full Paper by Stefano Sabatini et al. on page 1293 in Issue 16, 2017 (DOI: 10.1002/cmdc.201700286).

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