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      Effects of chlorogenic acid on antimicrobial, antivirulence, and anti-quorum sensing of carbapenem-resistant Klebsiella pneumoniae

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          Abstract

          The rise in infections caused by the hypervirulent carbapenem-resistant Klebsiella pneumoniae (hv-CRKP) is an emergent threat to public health. We assessed the effects of chlorogenic acid (CA), a natural phenolic compound, on antibacterial, antivirulence, and anti-quorum sensing (QS) of hv-CRKP. Five hv-CRKP were selected for antimicrobial susceptibility test and confirmed to carry virulence genes and carbapenem-resistant genes by polymerase chain reaction (PCR). Subsequently, a series of time-kill assay, determinations of protease activity and capsule content, biofilm-related experiment, scanning electron microscopy (SEM) and transmission electron microscope (TEM) observation, G. mellonella infection model, quantitative real-time PCR (qRT-PCR) of QS-related genes and biofilm formation genes, as well as AI-2 binding test were conduct to verify the effect of CA on hv-CRKP. Five CRKP strains showed varying degrees of resistance to antibacterial agents. All strains carried the bla KPC–2 gene, primarily carrying rmpA2, iucA, and peg-344. CA showed no effect on CRKP growth at the 1/2 minimum inhibitory concentration (MIC), 1/4 MIC, and 1/8 MIC, CA could reduce the production of extracellular protease and capsular polysaccharides, and improve the survival rate of larvae in Galleria mellonella ( G. mellonella) infection model. By means of crystal violet staining and scanning electron microscopy experiments, we observed that CA can inhibit the formation of CRKP biofilm. On the quantitative real-time PCR analysis, the expression of the luxS, mrkA and wbbm genes in most CRKP strains appeared downregulated because of the CA treatment. Besides, CA significantly inhibited the effect of AI-2 activity of BB170. Our study suggests that CA can be an effective antimicrobial, antivirulent compound that can target QS in hv-CRKP infections, thus providing a new therapeutic direction for treating bacterial infections.

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          Hypervirulent (hypermucoviscous) Klebsiella pneumoniae

          Alyssa S. Shon, Rajinder Bajwa, Thomas Russo (2013)
          A new hypervirulent (hypermucoviscous) variant of Klebsiella pneumoniae has emerged. First described in the Asian Pacific Rim, it now increasingly recognized in Western countries. Defining clinical features are the ability to cause serious, life-threatening community-acquired infection in younger healthy hosts, including liver abscess, pneumonia, meningitis and endophthalmitis and the ability to metastatically spread, an unusual feature for enteric Gram-negative bacilli in the non-immunocompromised. Despite infecting a healthier population, significant morbidity and mortality occurs. Although epidemiologic features are still being defined, colonization, particularly intestinal colonization, appears to be a critical step leading to infection. However the route of entry remains unclear. The majority of cases described to date are in Asians, raising the issue of a genetic predisposition vs. geospecific strain acquisition. The traits that enhance its virulence when compared with “classical” K. pneumoniae are the ability to more efficiently acquire iron and perhaps an increase in capsule production, which confers the hypermucoviscous phenotype. An objective diagnostic test suitable for routine use in the clinical microbiology laboratory is needed. If/when these strains become increasingly resistant to antimicrobials, we will be faced with a frightening clinical scenario.
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            Quorum sensing signal–response systems in Gram-negative bacteria

            Kai Papenfort, Bonnie Bassler (2016)
            Bacteria use quorum sensing to orchestrate gene expression programmes that underlie collective behaviours. Quorum sensing relies on the production, release, detection and group-level response to extracellular signalling molecules, which are called autoinducers. Recent work has discovered new autoinducers in Gram-negative bacteria, shown how these molecules are recognized by cognate receptors, revealed new regulatory components that are embedded in canonical signalling circuits and identified novel regulatory network designs. In this Review we examine how, together, these features of quorum sensing signal-response systems combine to control collective behaviours in Gram-negative bacteria and we discuss the implications for host-microbial associations and antibacterial therapy.
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              Hypervirulent Klebsiella pneumoniae

              Thomas Russo, Candace Marr (2019)
              Hypervirulent K. pneumoniae (hvKp) is an evolving pathotype that is more virulent than classical K. pneumoniae (cKp). hvKp usually infects individuals from the community, who are often healthy. Infections are more common in the Asian Pacific Rim but are occurring globally. hvKp infection frequently presents at multiple sites or subsequently metastatically spreads, often requiring source control. hvKp has an increased ability to cause central nervous system infection and endophthalmitis, which require rapid recognition and site-specific treatment. The genetic factors that confer hvKp’s hypervirulent phenotype are present on a large virulence plasmid and perhaps integrative conjugal elements. Increased capsule production and aerobactin production are established hvKp-specific virulence factors. Similar to cKp, hvKp strains are becoming increasingly resistant to antimicrobials via acquisition of mobile elements carrying resistance determinants, and new hvKp strains emerge when extensively drug-resistant cKp strains acquire hvKp-specific virulence determinants, resulting in nosocomial infection. Presently, clinical laboratories are unable to differentiate cKp from hvKp, but recently, several biomarkers and quantitative siderophore production have been shown to accurately predict hvKp strains, which could lead to the development of a diagnostic test for use by clinical laboratories for optimal patient care and for use in epidemiologic surveillance and research studies.
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                Author and article information

                Contributors
                Journal
                Journal ID (nlm-ta): Front Microbiol
                Journal ID (iso-abbrev): Front Microbiol
                Journal ID (publisher-id): Front. Microbiol.
                Title: Frontiers in Microbiology
                Publisher: Frontiers Media S.A.
                ISSN (Electronic): 1664-302X
                Publication date (Electronic): 13 December 2022
                Publication date Collection: 2022
                Volume: 13
                Electronic Location Identifier: 997310
                Affiliations
                [1] 1Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University and Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province , Wenzhou, Zhejiang, China
                [2] 2Department of Microbiology, Zhejiang Provincial Center for Disease Control and Prevention , Hangzhou, China
                [3] 3Department of Medical Lab Science, School of Laboratory Medicine and Life Science, Wenzhou Medical University , Wenzhou, Zhejiang, China
                Author notes

                Edited by: Manuela Mandrone, University of Bologna, Italy

                Reviewed by: Arindam Mitra, Adamas University, India; Po-Xing Zheng, Academia Sinica, Taiwan

                *Correspondence: Tieli Zhou, wyztli@ 123456163.com

                †These authors have contributed equally to this work

                This article was submitted to Antimicrobials, Resistance and Chemotherapy, a section of the journal Frontiers in Microbiology

                Article
                DOI: 10.3389/fmicb.2022.997310
                PMC ID: 9793747
                PubMed ID: 36583040
                SO-VID: 4ffee0e6-3651-456d-b3d9-3e362c2b1b45
                Copyright © Copyright © 2022 Wang, Zhang, Liu, Xu, Yao, Zhang, Sun, Zhou and Shen.
                License:

                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
                Date received : 18 July 2022
                Date accepted : 29 November 2022
                Page count
                Figures: 12, Tables: 1, Equations: 0, References: 52, Pages: 15, Words: 8518
                Categories
                Subject: Microbiology
                Subject: Original Research

                ScienceOpen disciplines: Microbiology & Virology
                Keywords: chlorogenic acid,carbapenem-resistant,hypervirulent,klebsiella pneumoniae,quorum sensing
                Data availability:
                ScienceOpen disciplines: Microbiology & Virology
                Keywords: chlorogenic acid, carbapenem-resistant, hypervirulent, klebsiella pneumoniae, quorum sensing

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