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      Antimicrobial Activity of a Repurposed Harmine-Derived Compound on Carbapenem-Resistant Acinetobacter baumannii Clinical Isolates

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          Abstract

          Objectives

          The spread of antibiotic resistant bacteria is an important threat for human health. Acinetobacter baumannii bacteria impose such a major issue, as multidrug- to pandrug-resistant strains have been isolated, rendering some infections untreatable. In this context, carbapenem-resistant A. baumannii bacteria were ranked as top priority by both WHO and CDC. In addition, A. baumannii bacteria survive in harsh environments, being capable of resisting to disinfectants and to persist prolonged periods of desiccation. Due to the high degree of variability found in A. baumannii isolates, the search for new antibacterials is very challenging because of the requirement of drug target conservation amongst the different strains. Here, we screened a chemical library to identify compounds active against several reference strains and carbapenem-resistant A. baumannii bacteria.

          Methods

          A repurposing drug screen was undertaken to identify A. baumannii growth inhibitors. One hit was further characterized by determining the IC 50 and testing the activity on 43 modern clinical A. baumannii isolates, amongst which 40 are carbapenem-resistant.

          Results

          The repurposing screen led to the identification of a harmine-derived compound, called HDC1, which proves to have bactericidal activity on the multidrug-resistant AB5075-VUB reference strain with an IC 50 of 48.23 µM. In addition, HDC1 impairs growth of 43 clinical A. baumannii isolates.

          Conclusions

          We identified a compound with inhibitory activity on all tested strains, including carbapenem-resistant clinical A. baumannii isolates.

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          Most cited references37

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          Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance.

          Many different definitions for multidrug-resistant (MDR), extensively drug-resistant (XDR) and pandrug-resistant (PDR) bacteria are being used in the medical literature to characterize the different patterns of resistance found in healthcare-associated, antimicrobial-resistant bacteria. A group of international experts came together through a joint initiative by the European Centre for Disease Prevention and Control (ECDC) and the Centers for Disease Control and Prevention (CDC), to create a standardized international terminology with which to describe acquired resistance profiles in Staphylococcus aureus, Enterococcus spp., Enterobacteriaceae (other than Salmonella and Shigella), Pseudomonas aeruginosa and Acinetobacter spp., all bacteria often responsible for healthcare-associated infections and prone to multidrug resistance. Epidemiologically significant antimicrobial categories were constructed for each bacterium. Lists of antimicrobial categories proposed for antimicrobial susceptibility testing were created using documents and breakpoints from the Clinical Laboratory Standards Institute (CLSI), the European Committee on Antimicrobial Susceptibility Testing (EUCAST) and the United States Food and Drug Administration (FDA). MDR was defined as acquired non-susceptibility to at least one agent in three or more antimicrobial categories, XDR was defined as non-susceptibility to at least one agent in all but two or fewer antimicrobial categories (i.e. bacterial isolates remain susceptible to only one or two categories) and PDR was defined as non-susceptibility to all agents in all antimicrobial categories. To ensure correct application of these definitions, bacterial isolates should be tested against all or nearly all of the antimicrobial agents within the antimicrobial categories and selective reporting and suppression of results should be avoided. © 2011 European Society of Clinical Microbiology and Infectious Diseases. No claim to original US government works.
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            Federal funding for the study of antimicrobial resistance in nosocomial pathogens: no ESKAPE.

            Louis Rice (2008)
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              Uncovering the mechanisms of Acinetobacter baumannii virulence

              Acinetobacter baumannii is a nosocomial pathogen that causes ventilator-associated as well as bloodstream infections in critically ill patients, and the spread of multidrug-resistant Acinetobacter strains is cause for concern. Much of the success of A. baumannii can be directly attributed to its plastic genome, which rapidly mutates when faced with adversity and stress. However, fundamental virulence mechanisms beyond canonical drug resistance were recently uncovered that enable A. baumannii and, to a limited extent, other medically relevant Acinetobacter species to successfully thrive in the health-care environment. In this Review, we explore the molecular features that promote environmental persistence, including desiccation resistance, biofilm formation and motility, and we discuss the most recently identified virulence factors, such as secretion systems, surface glycoconjugates and micronutrient acquisition systems that collectively enable these pathogens to successfully infect their hosts.
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                Author and article information

                Contributors
                Journal
                Front Cell Infect Microbiol
                Front Cell Infect Microbiol
                Front. Cell. Infect. Microbiol.
                Frontiers in Cellular and Infection Microbiology
                Frontiers Media S.A.
                2235-2988
                24 January 2022
                2021
                : 11
                : 789672
                Affiliations
                [1] 1 Microbial Resistance and Drug Discovery, Vlaams Instituut voor Biotechnologie-Vrije Universiteit Brussel (VIB-VUB) Center for Structural Biology, Vlaams Instituut voor Biotechnologie (VIB), Flanders Institute for Biotechnology , Brussels, Belgium
                [2] 2 Structural Biology Brussels, Vrije Universiteit Brussel (VUB) , Brussels, Belgium
                [3] 3 Namur Medicine and Drug Innovation Center (NAMEDIC), University of Namur (UNamur) , Namur, Belgium
                [4] 4 Research Group of Organic Chemistry, Departments of Chemistry and Bioengineering Sciences, Vrije Universiteit Brussel , Brussels, Belgium
                [5] 5 Research Unit in the Biology of Microorganisms (URBM), NARILIS, University of Namur (UNamur) , Namur, Belgium
                [6] 6 Laboratory of Evolutionary Genetics and Ecology, URBE, University of Namur (UNamur) , Namur, Belgium
                [7] 7 Molecular Biology and Evolution, Universite´ Libre de Bruxelles (ULB) , Brussels, Belgium
                Author notes

                Edited by: Brock Aaron Arivett, Middle Tennessee State University, United States

                Reviewed by: Rafael Franco-Cendejas, National Institute of Rehabilitation Luis Guillermo Ibarra Ibarra, Mexico; Steven Fiester, University of South Carolina, United States

                *Correspondence: Charles Van der Henst, charles.vanderhenst@ 123456vub.vib.be

                This article was submitted to Bacteria and Host, a section of the journal Frontiers in Cellular and Infection Microbiology

                Article
                10.3389/fcimb.2021.789672
                8819726
                8b08d1cc-e721-4e50-8a5b-69de8f05f306
                Copyright © 2022 Breine, Van Gysel, Elsocht, Whiteway, Philippe, Quinet, Valcek, Wouters, Ballet and Van der Henst

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 05 October 2021
                : 15 December 2021
                Page count
                Figures: 3, Tables: 1, Equations: 0, References: 37, Pages: 9, Words: 3917
                Funding
                Funded by: H2020 Marie Skłodowska-Curie Actions , doi 10.13039/100010665;
                Funded by: Fonds Wetenschappelijk Onderzoek , doi 10.13039/501100003130;
                Categories
                Cellular and Infection Microbiology
                Original Research

                Infectious disease & Microbiology
                acinetobacter baumannii,carbapenem-resistant,gram-negative,pathogenic bacteria,repurposed compound,drug screening

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