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      The Growing Genetic and Functional Diversity of Extended Spectrum Beta-Lactamases

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          Abstract

          The β-lactams—a large class of diverse compounds—due to their excellent safety profile and broad antimicrobial spectrum are considered to be the most widely used therapeutic class of antibacterials prescribed in human and veterinary clinical practices. This, unfortunately, has also given rise to a continuous increased resistance globally in health care settings as well as in the community due to their permanent selective force driving diversification of the resistance mechanism. Resistance against β-lactams is increasing rapidly as novel β-lactamases, enzymes that degrade β-lactams, are being discovered each day such as recent emergence of extended spectrum β-lactamases (ESBL) that have the ability to inactivate most of the cephalosporins. The complexity and diversity of ESBL are increasing so rapidly that more than 170 variants have thus far been described for only a single genotype, the bla CTX- M -encoding ESBL. This review is to organize all the current updated literature describing genomic features, organization, and mechanism of resistance and mode of dissemination of all known ESBLs.

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          Most cited references87

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          Outer membrane permeability and antibiotic resistance.

          To date most antibiotics are targeted at intracellular processes, and must be able to penetrate the bacterial cell envelope. In particular, the outer membrane of gram-negative bacteria provides a formidable barrier that must be overcome. There are essentially two pathways that antibiotics can take through the outer membrane: a lipid-mediated pathway for hydrophobic antibiotics, and general diffusion porins for hydrophilic antibiotics. The lipid and protein compositions of the outer membrane have a strong impact on the sensitivity of bacteria to many types of antibiotics, and drug resistance involving modifications of these macromolecules is common. This review will describe the molecular mechanisms for permeation of antibiotics through the outer membrane, and the strategies that bacteria have deployed to resist antibiotics by modifications of these pathways.
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            CTX-M Enzymes: Origin and Diffusion

            CTX-M β-lactamases are considered a paradigm in the evolution of a resistance mechanism. Incorporation of different chromosomal bla CTX-M related genes from different species of Kluyvera has derived in different CTX-M clusters. In silico analyses have shown that this event has occurred at least nine times; in CTX-M-1 cluster (3), CTX-M-2 and CTX-M-9 clusters (2 each), and CTX-M-8 and CTX-M-25 clusters (1 each). This has been mainly produced by the participation of genetic mobilization units such as insertion sequences (ISEcp1 or ISCR1) and the later incorporation in hierarchical structures associated with multifaceted genetic structures including complex class 1 integrons and transposons. The capture of these bla CTX-M genes from the environment by highly mobilizable structures could have been a random event. Moreover, after incorporation within these structures, β-lactam selective force such as that exerted by cefotaxime and ceftazidime has fueled mutational events underscoring diversification of different clusters. Nevertheless, more variants of CTX-M enzymes, including those not inhibited by β-lactamase inhibitors such as clavulanic acid (IR-CTX-M variants), only obtained under in in vitro experiments, are still waiting to emerge in the clinical setting. Penetration and the later global spread of CTX-M producing organisms have been produced with the participation of the so-called “epidemic resistance plasmids” often carried in multi-drug resistant and virulent high-risk clones. All these facts but also the incorporation and co-selection of emerging resistance determinants within CTX-M producing bacteria, such as those encoding carbapenemases, depict the currently complex pandemic scenario of multi-drug resistant isolates.
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              Integrons: agents of bacterial evolution.

              Integrons are assembly platforms - DNA elements that acquire open reading frames embedded in exogenous gene cassettes and convert them to functional genes by ensuring their correct expression. They were first identified by virtue of their important role in the spread of antibiotic-resistance genes. More recently, our understanding of their importance in bacterial genome evolution has broadened with the discovery of larger integron structures, termed superintegrons. These DNA elements contain hundreds of accessory genes and constitute a significant fraction of the genomes of many bacterial species. Here, the basic biology of integrons and superintegrons, their evolutionary history and the evidence for the existence of a novel recombination pathway is reviewed.
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                Author and article information

                Contributors
                Journal
                Biomed Res Int
                Biomed Res Int
                BMRI
                BioMed Research International
                Hindawi
                2314-6133
                2314-6141
                2018
                26 March 2018
                : 2018
                : 9519718
                Affiliations
                1Department of Clinical Veterinary Medicine, College of Veterinary Medicine, China Agricultural University, Beijing, China
                2Abdul Wali Khan University, Garden Campus, Khyber Pakhtunkhwa, Pakistan
                3Department of Biosciences, COMSATS Institute of Information Technology (CIIT), Bioscience Block, Chak Shahzad Campus, Park Road, Islamabad, Pakistan
                4Department of Animal Nutrition, The University of Agriculture, Peshawar, Pakistan
                Author notes

                Academic Editor: Yun-Peng Chao

                Author information
                http://orcid.org/0000-0002-9314-6257
                http://orcid.org/0000-0003-2163-8874
                http://orcid.org/0000-0002-8501-1942
                http://orcid.org/0000-0002-4798-7725
                http://orcid.org/0000-0001-5059-2698
                Article
                10.1155/2018/9519718
                5892270
                29780833
                cee46565-01c9-42fd-91e0-a86b7a1a1bf9
                Copyright © 2018 Sadeeq ur Rahman et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 2 November 2017
                : 24 January 2018
                : 31 January 2018
                Funding
                Funded by: National Natural Science Foundation of China
                Award ID: 31772813
                Award ID: 31572587
                Award ID: 31550110200
                Funded by: High-End Foreign Experts Recruitment Program
                Award ID: GDT20141100043
                Funded by: National Key R&D Program
                Award ID: 2016YFD0501203
                Categories
                Review Article

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