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      Antistaphylococcal evaluation of indole–naphthalene hybrid analogs

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          Abstract

          Resistance developments against established antibiotics are an emerging problem for antibacterial therapies. Infections with Staphylococcus aureus and methicillin-resistant S. aureus (MRSA) have become more difficult to treat with standard antibiotics that often fail, especially against MRSA. In consequence, novel antibiotics are urgently needed. Antibiotics from natural sources own complicated structures that cause difficulties for a chemical synthetic production. We developed novel small-molecule antibacterials that are easily accessible in a simple one-pot synthesis. The central indolonaphthalene core is substituted with indole residues at various positions. Both the varied indole substitutions and their positions at the molecular scaffold influence the determined antibacterial activity against the evaluated Staphylococcus strains. Best activities have been found for 5-chloro, -cyano, and -hydroxyl indole substitutions. Therefore, first promising lead compounds could be identified that are nontoxic in human HEK and SH-SY5Y cells and exceed the activity of used standard antibiotics, especially against MRSA.

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          Most cited references 23

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          Repair of global regulators in Staphylococcus aureus 8325 and comparative analysis with other clinical isolates.

          The pathogenicity of Staphylococcus aureus strains varies tremendously (as seen with animals). It is largely dependent on global regulators, which control the production of toxins, virulence, and fitness factors. Despite the vast knowledge of staphylococcal molecular genetics, there is still widespread dispute over what factors must come together to make a strain highly virulent. S. aureus NCTC8325 (RN1 and derivatives) is a widely used model strain for which an incomparable wealth of knowledge has accumulated in the almost 50 years since its isolation. Although RN1 has functional agr, sarA, and sae global regulators, it is defective in two regulatory genes, rsbU (a positive activator of SigB) and tcaR (an activator of protein A transcription), and is therefore considered by many to be a poor model for studies of regulation and virulence. Here, we repaired these genes and compared the resulting RN1 derivatives with other widely used strains, Newman, USA300, UAMS-1, and COL, plus the parental RN1, with respect to growth, extracellular protein pattern, hemolytic activity, protein A production, pigmentation, biofilm formation, and mouse lethality. The tcaR-repaired strain, showed little alteration in these properties. However, the rsbU-repaired strain was profoundly altered. Hemolytic activity was largely decreased, the exoprotein pattern became much more similar to that of typical wild-type (wt) S. aureus, and there was a surprising increase in mouse lethality. We note that each of the strains tested has a mutational alteration in one or more other regulatory functions, and we conclude that the repaired RN1 is a good model strain for studies of staphylococcal regulation and pathobiology; although strain Newman has been used extensively for such studies in recent years, it has a missense mutation in saeS, the histidine kinase component of the sae signaling module, which profoundly alters its regulatory phenotype. If this mutation were repaired, Newman would be considerably improved as a model strain.
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            Staphylococcal coagulase; mode of action and antigenicity.

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              Update on the antibiotic resistance crisis.

              Antibiotics tend to lose their efficacy over time due to the emergence and dissemination of resistance among bacterial pathogens. Strains with resistance to multiple antibiotic classes have emerged among major Gram-positive and Gram-negative species including Staphylococcus aureus, Enterococcus spp., Pseudomonas aeruginosa, Acinetobacter spp. Enterobacteriaceae, and Neisseria gonorrhoeae. With some Gram-negatives, resistance may involve most or even all the available antimicrobial options, resulting in extremely drug-resistant or totally drug-resistant phenotypes. This so-called 'antibiotic resistance crisis' has been compounded by the lagging in antibiotic discovery and development programs occurred in recent years, and is jeopardizing the essential role played by antibiotics in current medical practices. Copyright © 2014 Elsevier Ltd. All rights reserved.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2019
                10 January 2019
                : 13
                : 275-283
                Affiliations
                [1 ]Institute of Pharmacy, Martin Luther University Halle-Wittenberg, Halle, Germany, andreas.hilgeroth@ 123456pharmazie.uni-halle.de
                [2 ]Institute of Molecular Infection Biology, Julius Maximilians University Würzburg, Würzburg, Germany
                [3 ]Institute of Biochemistry, Ernst Moritz Arndt University Greifswald, Greifswald, Germany
                Author notes
                Correspondence: Andreas Hilgeroth, Institute of Pharmacy, Martin Luther University Halle-Wittenberg, Wolfgang Langenbeck Street 4, 06210 Halle, Germany, Tel +49 345 55 25168, Fax +49 345 55 27207, Email andreas.hilgeroth@ 123456pharmazie.uni-halle.de
                Article
                dddt-13-275
                10.2147/DDDT.S184965
                6331074
                © 2019 Ashraf et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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