Browsing by Subject "antibacterial"

Now showing 1 - 3 of 3
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    Discovery of potent and selective inhibitors of the Escherichia coli M1-aminopeptidase via multicomponent solid-phase synthesis of tetrazole-peptidomimetics
    (Elsevier, 2019-01) Méndez, Yanira; De Armas, German; Pérez, Idalia; Rojas, Tamara; Valdés-Tresanco, Mario E.; Izquierdo, Maikel; del Rivero, Maday Alonso; Álvarez-Ginarte, Yoanna María; Valiente, Pedro A.; Soto, Carmen; de León, Lena; Vasco, Aldrin V.; Scott, William L.; Westermann, Bernhard; González-Bacerio, Jorge; Rivera, Daniel G.; Chemistry and Chemical Biology, School of Science
    The Escherichia coli neutral M1-aminopeptidase (ePepN) is a novel target identified for the development of antimicrobials. Here we describe a solid-phase multicomponent approach which enabled the discovery of potent ePepN inhibitors. The on-resin protocol, developed in the frame of the Distributed Drug Discovery (D3) program, comprises the implementation of parallel Ugi-azide four-component reactions with resin-bound amino acids, thus leading to the rapid preparation of a focused library of tetrazole-peptidomimetics (TPMs) suitable for biological screening. By dose-response studies, three compounds were identified as potent and selective ePepN inhibitors, as little inhibitory effect was exhibited for the porcine ortholog aminopeptidase. The study allowed for the identification of the key structural features required for a high ePepN inhibitory activity. The most potent and selective inhibitor (TPM 11) showed a non-competitive inhibition profile of ePepN. We predicted that both diastereomers of compound TPM 11 bind to a site distinct from that occupied by the substrate. Theoretical models suggested that TPM 11 has an alternative inhibition mechanism that doesn't involve Zn coordination. On the other hand, the activity landscape analysis provided a rationale for our findings. Of note, compound TMP 2 showed in vitro antibacterial activity against Escherichia coli. Furthermore, none of the three identified inhibitors is a potent haemolytic agent, and only two compounds showed moderate cytotoxic activity toward the murine myeloma P3X63Ag cells. These results point to promising compounds for the future development of rationally designed TPMs as antibacterial agents.
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    First-generation structure-activity relationship studies of 2,3,4,9-tetrahydro-1H-carbazol-1-amines as CpxA phosphatase inhibitors
    (Elsevier, 2019-07) Li, Yangxiong; Gardner, Jessi J.; Fortney, Katherine R.; Leus, Inga V.; Bonifay, Vincent; Zgurskaya, Helen I.; Pletnev, Alexandre A.; Zhang, Sheng; Zhang, Zhong-Yin; Gribble, Gordon W.; Spinola, Stanley M.; Duerfeldt, Adam S.; Microbiology and Immunology, School of Medicine
    Genetic activation of the bacterial two-component signal transduction system, CpxRA, abolishes the virulence of a number of pathogens in human and murine infection models. Recently, 2,3,4,9-tetrahydro-1H-carbazol-1-amines were shown to activate the CpxRA system by inhibiting the phosphatase activity of CpxA. Herein we report the initial structure-activity relationships of this scaffold by focusing on three approaches 1) A-ring substitution, 2) B-ring deconstruction to provide N-arylated amino acid derivatives, and 3) C-ring elimination to give 2-ethylamino substituted indoles. These studies demonstrate that the A-ring is amenable to functionalization and provides a promising avenue for continued optimization of this chemotype. Further investigations revealed that the C-ring is not necessary for activity, although it likely provides conformational constraint that is beneficial to potency, and that the (R) stereochemistry is required at the primary amine. Simplification of the scaffold through deconstruction of the B-ring led to inactive compounds, highlighting the importance of the indole core. A new lead compound 26 was identified, which manifests a ∼30-fold improvement in CpxA phosphatase inhibition over the initial hit. Comparison of amino and des-amino derivatives in bacterial strains differing in membrane permeability and efflux capabilities demonstrate that the amine is required not only for target engagement but also for permeation and accumulation in Escherichia coli.
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    Low-Temperature Plasma as an Approach for Inhibiting a Multi-Species Cariogenic Biofilm
    (MDPI, 2020-01) Figueira, Leandro W.; Panariello, Beatriz H. D.; Koga-Ito, Cristiane Y.; Duarte, Simone; Cariology, Operative Dentistry and Dental Public Health, School of Dentistry
    This study aimed to determine how low-temperature plasma (LTP) treatment affects single- and multi-species biofilms formed by Streptococcus mutans, Streptococcus sanguinis, and Streptococcus gordonii formed on hydroxyapatite discs. LTP was produced by argon gas using the kINPen09™ (Leibniz Institute for Plasma Science and Technology, INP, Greifswald, Germany). Biofilms were treated at a 10 mm distance from the nozzle of the plasma device to the surface of the biofilm per 30 s, 60 s, and 120 s. A 0.89% saline solution and a 0.12% chlorhexidine solution were used as negative and positive controls, respectively. Argon flow at three exposure times (30 s, 60 s, and 120 s) was also used as control. Biofilm viability was analyzed by colony-forming units (CFU) recovery and confocal laser scanning microscopy. Multispecies biofilms presented a reduction in viability (log10 CFU/mL) for all plasma-treated samples when compared to both positive and negative controls (p < 0.0001). In single-species biofilms formed by either S. mutans or S. sanguinis, a significant reduction in all exposure times was observed when compared to both positive and negative controls (p < 0.0001). For single-species biofilms formed by S. gordonii, the results indicate total elimination of S. gordonii for all exposure times. Low exposure times of LTP affects single- and multi-species cariogenic biofilms, which indicates that the treatment is a promising source for the development of new protocols for the control of dental caries.