Porin Deficiency in Carbapenem-Resistant<i>Enterobacter aerogenes</i>Strains

Hao, Min; Ye, Meiping; Shen, Zhen; Hu, Fupin; Yang, Yang; Shi, Wei; Xu, Xiaogang; Zhu, Sihui; Qin, Xiaohua; Wang, Minggui

doi:10.1089/mdr.2017.0379

Cited by 31 publications

(32 citation statements)

References 26 publications

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“…Thus, further studies are needed to understand the pathways of regulation for resistance-related genes in K. pneumoniae during antibiotic pressure. A recent study revealed that in vitro carbapenem resistance induction could lead the loss of OmpK 36 in induced isolate after several days of serial passaging [51]. In this study, we reported a link between a 14-day imipenem treatment and the loss of OmpK 36 in vivo.…”

Section: Discussionsupporting

confidence: 52%

First description of antimicrobial resistance in carbapenem-susceptible Klebsiella pneumoniae after imipenem treatment, driven by outer membrane remodeling

Tian

Wang

New

et al. 2020

Preprint

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Background:The emergence of carbapenem-resistant Klebsiella pneumoniae (CRKP) poses a looming threat to human health. Although there are numerous studies regarding porin alteration in association with the production of ESBLs and/or AmpC β-lactamase, a systematic study on the treatment-emergence of porins alteration in antibiotic resistance does not yet exist. The aim of this study was to investigate the underlying mechanism and evolution of resistance of K. pneumoniae during carbapenem treatment. Results:Here, we report three strains (FK-2624, FK-2723 and FK-2820) isolated from one patient before and after imipenem treatment during hospitalization. Antibiotic susceptibility testing indicated that that the first isolate, FK-2624, was susceptible to almost all tested antimicrobials, being resistant only to fosfomycin. The subsequent isolates FK-2723 and FK-2820 were multidrug resistant (MDR). After imipenem therapy, FK-2820 had evolved to be carbapenem-resistant. PCR and Genome Sequencing analysis indicated that oqxA, and fosA5, were identified in all three strains. In addition, FK-2624 also harbored bla SHV-187 and blaTEM-116. The blaSHV-187 and blaTEM-116 genes were not detected in FK-2723 and FK-2820. blaDHA-1, qnrB4, aac (6’)-IIc, and blaSHV-12, EreA2, CatA2, SulI, and tetD , were identified in both FK-2723 and FK-2820. Moreover, the genes bla DHA -1, qnrB4, aac(6’)-IIc were co-harbored on a plasmid. Of the virulence factors found in this study, ybtA, ICEKp6, mrkD, entB, iroN, rmpA2-6, wzi16 and capsular serotype K57 were found in the three isolates. The results of pairwise comparisons, multi-locus sequencing typing (MLST) and pulsed-field gel electrophoresis (PFGE) revealed high homology among the isolates. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) results showed that isolate FK-2820 lacked OmpK36, with genome sequence data validating that there was a premature stop codon in the ompK36 gene and real-time RT-PCR suggesting high turnover of the ompK36 non-sense transcript in FK-2820, with the steady-state mRNA level 0.007 relative to the initial isolate. Conclusion:This study in China highlight that the alteration of outer membrane porins due to the 14-day use of imipenem play a potential role in leading to clinical presentation of carbapenem-resistance. This is the first description of increased resistance developing from a carbapenem-susceptible K. pneumoniae with imipenem treatment driven by outer membrane remodeling.

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Section: Discussionsupporting

confidence: 52%

First description of antimicrobial resistance in carbapenem-susceptible Klebsiella pneumoniae after imipenem treatment, driven by outer membrane remodeling

Tian

Wang

New

et al. 2020

Preprint

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“…Thus, further studies are needed to understand the pathways of regulation for resistance-related genes in K. pneumoniae during antibiotic pressure. A recent study revealed that a 13-day in vitro carbapenem resistance induction showed loss of OmpK 36 in mutant isolate [21]. In current study, our data showed that a 14-day treatment in vivo of MDR K. pneumoniae infection was not particularly effective in clearing MDR K. pneumoniae the sputum.…”

Section: Discussioncontrasting

confidence: 46%

First description of antimicrobial resistance in carbapenem-susceptible Klebsiella pneumoniae after imipenem treatment, driven by outer membrane remodeling

et al. 2020

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Background: The emergence of carbapenem-resistant Klebsiella pneumoniae (CRKP) poses a looming threat to human health. Although there are numerous studies regarding porin alteration in association with the production of ESBLs and/or AmpC β-lactamase, a systematic study on the treatment-emergence of porins alteration in antibiotic resistance does not yet exist. The aim of this study was to investigate the underlying mechanism of resistance of K. pneumoniae during carbapenem treatment. Results: Here, we report three strains (FK-2624, FK-2723 and FK-2820) isolated from one patient before and after imipenem treatment during hospitalization. Antibiotic susceptibility testing indicated that that the first isolate, FK-2624, was susceptible to almost all tested antimicrobials, being resistant only to fosfomycin. The subsequent isolates FK-2723 and FK-2820 were multidrug resistant (MDR). After imipenem therapy, FK-2820 was found to be carbapenem-resistant. PCR and Genome Sequencing analysis indicated that oqxA, and fosA5, were identified in all three strains. In addition, FK-2624 also harbored bla SHV-187 and bla TEM-116. The bla SHV-187 and bla TEM-116 genes were not detected in FK-2723 and FK-2820. bla DHA-1 , qnrB4, aac (6′)-IIc, and bla SHV-12 , EreA2, CatA2, SulI, and tetD, were identified in both FK-2723 and FK-2820. Moreover, the genes bla DHA-1, qnrB4, aac (6′)-IIc were co-harbored on a plasmid. Of the virulence factors found in this study, ybtA, ICEKp6, mrkD, entB, iroN, rmpA2-6, wzi16 and capsular serotype K57 were found in the three isolates. The results of pairwise comparisons, multi-locus sequencing typing (MLST) and pulsed-field gel electrophoresis (PFGE) revealed high homology among the isolates. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) results showed that isolate FK-2820 lacked OmpK36, with genome sequence data validating that there was a premature stop codon in the ompK36 gene and real-time RT-PCR suggesting high turnover of the ompK36 nonsense transcript in FK-2820, with the steady-state mRNA level 0.007 relative to the initial isolate.

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“…The regulation systems are also responsible for a rapid adaptation following external stresses such as antibiotics, chemicals, and colicins 1,6 . It should be stressed that only few studies have studied a possible role of MicF and MicC in the alteration of OM permeability in resistant strains [145][146][147] In the case of uncharged molecules, electro-osmosis can be considered 148 Computer modelling can nowadays predict the energy barrier of a molecule along the channel axis which allows to obtain an estimate for the flux. In the above figure we show the free-energy surface of avibactam along the Z axis of diffusion and, for a comparison with free energies of Cl−and Na+ ions, calculated using their relative densities with respect to the bulk.…”

Section: Discussionmentioning

confidence: 99%

Porins and small-molecule translocation across the outer membrane of Gram-negative bacteria

Vergalli¹,

Bodrenko²,

Masi³

et al. 2019

Nat Rev Microbiol

262

260

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Gram-negative bacteria and their complex cell envelope comprising an outer and inner membrane are an important and attractive system for studying the translocation of small molecules across biological membranes. In the outer membrane of Enterobacteriaceae, trimeric porins control the cellular penetration of small molecules, including nutrients and antibacterial agents. The synergistic action between relatively slow porin-mediated passive uptake across the outer membrane and active efflux transporters in the inner membrane creates a permeability barrier that reinforces the enzymatic modification barrier, which efficiently reduces the intracellular concentrations of small molecules and contributes to the emergence of antibiotic resistance. In this review, we discuss recent advances in our understanding of the molecular and functional roles of classic porins in small molecule translocation in Enterobacteriaceae and consider the crucial role of porins in antibiotic resistance. Commented [w1]: Is this specification necessary here?, in my opinion it deviates, better to put later… Commented [JP2]: Editor request... porins represent the preferred route for the entry of β-lactams, including cephalosporins, penicillins and carbapenems 14-16. The clinical relevance of membrane-associated mechanisms (MAMs) of resistance (i.e. porin defects and/or overexpression of multidrug efflux pumps) has been well established for these antibiotics. The Influx and Efflux rates control the internal concentration of antibiotics and represent the first lane (mechanical barrier) protecting the bacterial cells against therapeutic treatment 1-3,6. Consequently, studies on bacterial porins are receiving a renewed interest due to their key role in the bacterial susceptibility towards clinically used antibiotics. In combination with the expression of antibiotic-modifying enzymes expressed in the periplasm (e.g. β-lactamases), porins play a key role in β-lactam resistance 4,17. In this review, we discuss recent advances in our understanding of the molecular and functional roles of classic porins in antibiotic translocation in Enterobacteriaceae. We explore structural aspects and the insights gained into permeation and the pore translocation process, the regulation of porin expression as well as the role of porins in the emergence of antibiotic susceptibility. Enterobacterial general porins Structural aspects The crystal structures of a general porin from Rhodobacter capsulatus 18 , the OmpF and PhoE porins from E. coli 19 and other E. coli OmpF structures including mutants 20,21 were the first to be solved. Only a limited number of other enterobacterial porin structures have been reported, i.e. E. coli OmpC, K. pneumoniae OmpK36 and Salmonella typhi OmpF 22-24. The lack of data has hindered attempts to relate structure to function. Recently, the structures of two porins from P. stuartii as well as the structures of the OmpF and OmpC orthologs of K. pneumoniae, E. aerogenes and E. cloacae have been reported 12,25,26. Another recent study reported th...

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Porin Deficiency in Carbapenem-ResistantEnterobacter aerogenesStrains

Cited by 31 publications

References 26 publications

First description of antimicrobial resistance in carbapenem-susceptible Klebsiella pneumoniae after imipenem treatment, driven by outer membrane remodeling

First description of antimicrobial resistance in carbapenem-susceptible Klebsiella pneumoniae after imipenem treatment, driven by outer membrane remodeling

First description of antimicrobial resistance in carbapenem-susceptible Klebsiella pneumoniae after imipenem treatment, driven by outer membrane remodeling

Porins and small-molecule translocation across the outer membrane of Gram-negative bacteria

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