Two Component Regulatory Systems and Antibiotic Resistance in Gram-Negative Pathogens

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Abstract

Gram-negative pathogens such as Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa are the leading cause of nosocomial infections throughout the world. One commonality shared among these pathogens is their ubiquitous presence, robust host-colonization and most importantly, resistance to antibiotics. A significant number of two-component systems (TCSs) exist in these pathogens, which are involved in regulation of gene expression in response to environmental signals such as antibiotic exposure. While the development of antimicrobial resistance is a complex phenomenon, it has been shown that TCSs are involved in sensing antibiotics and regulating genes associated with antibiotic resistance. In this review, we aim to interpret current knowledge about the signaling mechanisms of TCSs in these three pathogenic bacteria. We further attempt to answer questions about the role of TCSs in antimicrobial resistance. We will also briefly discuss how specific two-component systems present in K. pneumoniae, A. baumannii, and P. aeruginosa may serve as potential therapeutic targets.

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Aminoglycoside antibiotics induce bacterial biofilm formation.

Lucas Hoffman, David D'Argenio, Michael MacCoss … (2005)

Biofilms are adherent aggregates of bacterial cells that form on biotic and abiotic surfaces, including human tissues. Biofilms resist antibiotic treatment and contribute to bacterial persistence in chronic infections. Hence, the elucidation of the mechanisms by which biofilms are formed may assist in the treatment of chronic infections, such as Pseudomonas aeruginosa in the airways of patients with cystic fibrosis. Here we show that subinhibitory concentrations of aminoglycoside antibiotics induce biofilm formation in P. aeruginosa and Escherichia coli. In P. aeruginosa, a gene, which we designated aminoglycoside response regulator (arr), was essential for this induction and contributed to biofilm-specific aminoglycoside resistance. The arr gene is predicted to encode an inner-membrane phosphodiesterase whose substrate is cyclic di-guanosine monophosphate (c-di-GMP)-a bacterial second messenger that regulates cell surface adhesiveness. We found that membranes from arr mutants had diminished c-di-GMP phosphodiesterase activity, and P. aeruginosa cells with a mutation changing a predicted catalytic residue of Arr were defective in their biofilm response to tobramycin. Furthermore, tobramycin-inducible biofilm formation was inhibited by exogenous GTP, which is known to inhibit c-di-GMP phosphodiesterase activity. Our results demonstrate that biofilm formation can be a specific, defensive reaction to the presence of antibiotics, and indicate that the molecular basis of this response includes alterations in the level of c-di-GMP.

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BLAST-EXPLORER helps you building datasets for phylogenetic analysis

Alexis Dereeper, Stéphane Audic, Jean-Michel Claverie … (2010)

Background The right sampling of homologous sequences for phylogenetic or molecular evolution analyses is a crucial step, the quality of which can have a significant impact on the final interpretation of the study. There is no single way for constructing datasets suitable for phylogenetic analysis, because this task intimately depends on the scientific question we want to address, Moreover, database mining softwares such as BLAST which are routinely used for searching homologous sequences are not specifically optimized for this task. Results To fill this gap, we designed BLAST-Explorer, an original and friendly web-based application that combines a BLAST search with a suite of tools that allows interactive, phylogenetic-oriented exploration of the BLAST results and flexible selection of homologous sequences among the BLAST hits. Once the selection of the BLAST hits is done using BLAST-Explorer, the corresponding sequence can be imported locally for external analysis or passed to the phylogenetic tree reconstruction pipelines available on the Phylogeny.fr platform. Conclusions BLAST-Explorer provides a simple, intuitive and interactive graphical representation of the BLAST results and allows selection and retrieving of the BLAST hit sequences based a wide range of criterions. Although BLAST-Explorer primarily aims at helping the construction of sequence datasets for further phylogenetic study, it can also be used as a standard BLAST server with enriched output. BLAST-Explorer is available at http://www.phylogeny.fr

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Past and Present Perspectives on β-Lactamases

Karen Bush (2018)

β-Lactamases, the major resistance determinant for β-lactam antibiotics in Gram-negative bacteria, are ancient enzymes whose origins can be traced back millions of years. These well-studied enzymes, currently numbering almost 2800 unique proteins, initially emerged from environmental sources, most likely to protect a producing bacterium from attack by naturally-occurring β-lactams. Their ancestors were presumably penicillin-binding proteins that share sequence homology with β-lactamases possessing an active site serine. Metallo-β-lactamases also exist, with one, or two, catalytically functional zinc ions. Although penicillinases in Gram-positive bacteria were reported shortly after penicillin was introduced clinically, transmissible β-lactamases that could hydrolyze recently-approved cephalosporins, monobactams and carbapenems later became important in Gram-negative pathogens. Nomenclature is based on one of two major systems. Originally, functional classifications were used, based on substrate and inhibitor profiles. A later scheme classifies β-lactamases according to amino acid sequences, resulting in class A, B, C and D enzymes. A more recent nomenclature combines the molecular and biochemical classifications into 17 functional groups that describe most β-lactamases. Some of the most problematic enzymes in the clinical community include extended-spectrum β-lactamases (ESBLs) and the serine and metallo-carbapenemases, all of which are at least partially addressed with new β-lactamase inhibitor combinations. New enzyme variants continue to be described, partly because of the ease of obtaining sequence data from whole genome sequencing studies. Often these new enzymes are devoid of any phenotypic descriptions, making it more difficult for clinicians and antibiotic researchers to address new challenges that may be posed by unusual β-lactamases.

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Journal

Journal ID (nlm-ta): Int J Mol Sci

Journal ID (iso-abbrev): Int J Mol Sci

Journal ID (publisher-id): ijms

Title: International Journal of Molecular Sciences

Publisher: MDPI

ISSN (Electronic): 1422-0067

Publication date (Electronic): 10 April 2019

Publication date Collection: April 2019

Volume: 20

Issue: 7

Electronic Location Identifier: 1781

Affiliations

[1 ]Department of Oral Biology, Rady Faculty of Health Sciences, University of Manitoba, 780 Bannatyne Ave, Winnipeg, MB R3E 0J9, Canada; anjalibhagirath@ 123456gmail.com (A.Y.B.); liy34544@ 123456myumanitoba.ca (Y.L.); Katherine.Yerex@ 123456umanitoba.ca (K.Y.); Xiaoxue.Ma@ 123456umanitoba.ca (X.M.)

[2 ]Department of Microbiology, Faculty of Sciences, University of Manitoba, Winnipeg, MB R3E 0J9, Canada; Rakesh.Patidar@ 123456umanitoba.ca

[3 ]Department of Medical Microbiology & Infectious Diseases, Rady Faculty of Health Sciences, University of Manitoba, 780 Bannatyne Ave, Winnipeg, MB R3E 0J9, Canada

Author notes

[* ]Correspondence: Ayush.Kumar@ 123456umanitoba.ca (A.K.); Kangmin.Duan@ 123456umanitoba.ca (K.D.)

[†]

Authors have contributed equally to this work.

Author information

Rakesh Patidar https://orcid.org/0000-0003-4857-2772

Ayush Kumar https://orcid.org/0000-0001-6395-7932

Kangmin Duan https://orcid.org/0000-0002-3016-786X

Article

Publisher ID: ijms-20-01781

DOI: 10.3390/ijms20071781

PMC ID: 6480566

PubMed ID: 30974906

SO-VID: cb5eee95-8792-4c1c-bebd-e4ffed83f525

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Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

Two Component Regulatory Systems and Antibiotic Resistance in Gram-Negative Pathogens

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Most cited references 245

Aminoglycoside antibiotics induce bacterial biofilm formation.

BLAST-EXPLORER helps you building datasets for phylogenetic analysis

Past and Present Perspectives on β-Lactamases

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