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      Carbonyl Cyanide m-Chlorophenylhydrazine (CCCP) Reverses Resistance to Colistin, but Not to Carbapenems and Tigecycline in Multidrug-Resistant Enterobacteriaceae

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          Abstract

          Background: Carbapenems (CAR), colistin (CST), and tigecycline (TGC) alone or in combination therapy has become the last-resort antibiotics for treating infections caused by multidrug resistant (MDR) bacteria. However, resistance to these reserve antibiotics are increasingly being reported worldwide. Hence, the quest to find other agents that will synergistically restore the efficacy of these antibiotics have increased.

          Methods: Sixty-three clinical Enterobacteriaceae isolates comprising of Klebsiella pneumoniae ( n = 24), Enterobacter spp. ( n = 15), Serratia marcescens ( n = 12), Citrobacter freundii ( n = 8), Escherichia coli ( n = 2), and K. oxytoca/michiganensis ( n = 2) with known carbapenem resistance mechanisms and undescribed CST and TGC resistance mechanisms were subjected to broth microdilution and meropenem (MEM) disc synergy test in the presence and absence of carbonyl cyanide m-chlorophenylhydrazine (CCCP), a H + conductor (protonophore).

          Results and conclusions: Susceptibility to MEM, imipenem (IMP), CST, and TGC was found in only 2, 0, 17, and 9 isolates respectively. Addition of CCCP reversed resistance to CST, TGC, IMP, and MEM in 44, 3, 0, and 0 isolates respectively; CST had the highest mean minimum inhibitory concentration (MIC) fold change (193.12; p < 0.0001) post CCCP compared to that of MEM (1.70), IMP (1.49) and TGC (1.16). Eight isolates tested positive for the MEM-CCCP disc synergy test. We concluded that CCCP reverse CST resistance in CST-resistant Enterobacteriaceae. Although CCCP is an experimental agent with no therapeutic value clinically, further studies are necessary to decipher the mechanisms underlying the CST-CCCP synergy to inform the development of adjuvants that could be therapeutically effective in CST-resistant infections.

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          Most cited references18

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          “Stormy waters ahead”: global emergence of carbapenemases

          Carbapenems, once considered the last line of defense against of serious infections with Enterobacteriaceae, are threatened with extinction. The increasing isolation of carbapenem-resistant Gram-negative pathogens is forcing practitioners to rely on uncertain alternatives. As little as 5 years ago, reports of carbapenem resistance in Enterobacteriaceae, common causes of both community and healthcare-associated infections, were sporadic and primarily limited to case reports, tertiary care centers, intensive care units, and outbreak settings. Carbapenem resistance mediated by β-lactamases, or carbapenemases, has become widespread and with the paucity of reliable antimicrobials available or in development, international focus has shifted to early detection and infection control. However, as reports of Klebsiella pneumoniae carbapenemases, New Delhi metallo-β-lactamase-1, and more recently OXA-48 (oxacillinase-48) become more common and with the conveniences of travel, the assumption that infections with highly resistant Gram-negative pathogens are limited to the infirmed and the heavily antibiotic and healthcare exposed are quickly being dispelled. Herein, we provide a status report describing the increasing challenges clinicians are facing and forecast the “stormy waters” ahead.
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            Recent advances toward a molecular mechanism of efflux pump inhibition

            Multidrug resistance (MDR) in Gram-negative pathogens, such as the Enterobacteriaceae and Pseudomonas aeruginosa, poses a significant threat to our ability to effectively treat infections caused by these organisms. A major component in the development of the MDR phenotype in Gram-negative bacteria is overexpression of Resistance-Nodulation-Division (RND)-type efflux pumps, which actively pump antibacterial agents and biocides from the periplasm to the outside of the cell. Consequently, bacterial efflux pumps are an important target for developing novel antibacterial treatments. Potent efflux pump inhibitors (EPIs) could be used as adjunctive therapies that would increase the potency of existing antibiotics and decrease the emergence of MDR bacteria. Several potent inhibitors of RND-type efflux pump have been reported in the literature, and at least three of these EPI series were optimized in a pre-clinical development program. However, none of these compounds have been tested in the clinic. One of the major hurdles to the development of EPIs has been the lack of biochemical, computational, and structural methods that could be used to guide rational drug design. Here, we review recent reports that have advanced our understanding of the mechanism of action of several potent EPIs against RND-type pumps.
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              Colistin and tigecycline resistance in carbapenemase-producing Gram-negative bacteria: emerging resistance mechanisms and detection methods.

              A literature review was undertaken to ascertain the molecular basis for tigecycline and colistin resistance mechanisms and the experimental basis for the detection and delineation of this resistance particularly in carbapenemase-producing Gram-negative bacteria. Pubmed, Google Scholar and Science Direct were searched with the keywords colistin, tigecycline, resistance mechanisms and detection methods. Trans-complementation and comparative MIC studies, mass spectrometry, chromatography, spectrofluorometry, PCR, qRT-PCR and whole genome sequencing (WGS) were commonly used to determine tigecycline and colistin resistance mechanisms, specifically modifications in the structural and regulatory efflux (acrAB, OqxAB, kpgABC adeABC-FGH-IJK, mexAB-XY-oprJM and soxS, rarA robA, ramRAB marRABC, adeLRS, mexRZ and nfxb) and lipid A (pmrHFIJFKLM, lpxA, lpxC lpxD and mgrB, pmrAB, phoPQ,) genes respectively. Mutations in the ribosomal 16S rRNA operon rrnBC, also yielded resistance to tigecycline through target site modifications. The mcr-1 gene conferring resistance to colistin was identified via WGS, trans-complementation and a murine thigh infection model studies. Common detection methods are mainly antibiotic sensitivity testing with broth microdilution while molecular identification tools are mostly PCR and WGS. Spectrofluorometry, MALDI-TOF MS, micro-array and real-time multiplex PCR hold much promise for the future as new detection tools.
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                Author and article information

                Contributors
                Journal
                Front Microbiol
                Front Microbiol
                Front. Microbiol.
                Frontiers in Microbiology
                Frontiers Media S.A.
                1664-302X
                14 February 2017
                2017
                : 8
                : 228
                Affiliations
                [1] 1Division of Microbiology, Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kwame Nkrumah University of Science and Technology Kumasi, Ghana
                [2] 2Discipline of Pharmaceutical Sciences, School of Health Sciences, University of KwaZulu-Natal Durban, South Africa
                [3] 3Biomedical Resource Unit, School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal Durban, South Africa
                Author notes

                Edited by: Yuji Morita, Aichi Gakuin University, Japan

                Reviewed by: Xian-Zhi Li, Health Canada, Canada; Juerg Dreier, Basilea Pharmaceutica, Switzerland; Alexandros Ikonomidis, BIOGONIDIAKI-Center of Infertility Investigation and Genetic Research, Greece

                *Correspondence: John Osei Sekyere jod14139@ 123456yahoo.com

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

                Article
                10.3389/fmicb.2017.00228
                5306282
                28261184
                375d7b18-1e7b-4dca-8d4f-c7f96595bc6a
                Copyright © 2017 Osei Sekyere and Amoako.

                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) or licensor 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
                : 30 November 2016
                : 01 February 2017
                Page count
                Figures: 1, Tables: 1, Equations: 1, References: 28, Pages: 9, Words: 6300
                Categories
                Microbiology
                Original Research

                Microbiology & Virology
                carbapenem,efflux pumps,colistin,cccp,protonophore,tigecycline
                Microbiology & Virology
                carbapenem, efflux pumps, colistin, cccp, protonophore, tigecycline

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