Reduced susceptibility to carbapenems in Klebsiella pneumoniae clinical isolates associated with plasmid-mediated β-lactamase production and OmpK36 porin deficiency

Wang, Xuanding; Cai, Jiachang; Hong, Zhou; Zhang, Rong; Chen, Gongxiang

doi:10.1099/jmm.0.008094-0

Cited by 69 publications

(49 citation statements)

References 33 publications

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“…Strains deficient in both OmpK35 and OmpK36 and containing carbapenem-hydrolyzing ␤-lactamase are obviously resistant to ertapenem (54). However, in 2009, clinical ertapenem-resistant strains lacking OmpK36 but not OmpK35 were reported in China (55). This is surprising, because OmpK35 should be able to allow an influx of this compound (MW, 475), although OmpK36 may also make significant contribution in view of its not-so-large size.…”

Section: Discussionmentioning

confidence: 67%

Klebsiella pneumoniae Major Porins OmpK35 and OmpK36 Allow More Efficient Diffusion of β-Lactams than Their Escherichia coli Homologs OmpF and OmpC

2016

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Klebsiella pneumoniae, one of the most important nosocomial pathogens, is becoming a major problem in health care because of its resistance to multiple antibiotics, including cephalosporins of the latest generation and, more recently, even carbapenems. This is largely due to the spread of plasmid-encoded extended-spectrum ␤-lactamases. However, antimicrobial agents must first penetrate the outer membrane barrier in order to reach their targets, and hydrophilic and charged ␤-lactams presumably diffuse through the porin channels. Unfortunately, the properties of K. pneumoniae porin channels are largely unknown. In this study, we made clean deletions of K. pneumoniae porin genes ompK35 and ompK36 and examined the antibiotic susceptibilities and diffusion rates of ␤-lactams. The results showed that OmpK35 and OmpK36 produced larger more permeable channels than their Escherichia coli homologs OmpF and OmpC; OmpK35 especially produced a diffusion channel of remarkably high permeability toward lipophilic (benzylpenicillin) and large (cefepime) compounds. These results were also confirmed by expressing various porins in an E. coli strain lacking major porins and the major multidrug efflux pump AcrAB. Our data explain why the development of drug resistance in K. pneumoniae is so often accompanied by the mutational loss of its porins, especially OmpK35, in addition to the various plasmid-carried genes of antibiotic resistance, because even hydrolysis by ␤-lactamases becomes inefficient in producing high levels of resistance if the bacterium continues to allow a rapid influx of ␤-lactams through its wide porin channels. IMPORTANCEIn Gram-negative bacteria, drugs must first enter the outer membrane, usually through porin channels. Thus, the quantitative examination of influx rates is essential for the assessment of resistance mechanisms, yet no such studies exist for a very important nosocomial pathogen, Klebsiella pneumoniae. We found that the larger channel porin of this organism, OmpK35, produces a significantly larger channel than its Escherichia coli homolog, OmpF. This makes unmodified K. pneumoniae strains more susceptible to relatively large antibiotics, such as the third-and fourth-generation cephalosporins. Also, even the acquisition of powerful ␤-lactamases is not likely to make them fully resistant in the presence of such an effective influx process, explaining why so many clinical isolates of this organism lack porins. K lebsiella pneumoniae is currently one of the most important Gram-negative nosocomial pathogens, which are often carbapenem resistant (1), and its wide dissemination is helped by its capacity to survive in the hospital environment (2), presumably aided by the production of thick capsules. A remarkable feature of multidrug-resistant isolates of this species is the absence of porin(s) (for an early report, see reference 3, and for reviews, see references 4 and 5). K. pneumoniae produces two classical trimeric porins, OmpK35 and OmpK36, which are homologs of OmpF and OmpC of Escherichia col...

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Section: Discussionmentioning

confidence: 67%

Klebsiella pneumoniae Major Porins OmpK35 and OmpK36 Allow More Efficient Diffusion of β-Lactams than Their Escherichia coli Homologs OmpF and OmpC

2016

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“…The majority of resistant Klebsiella isolates exhibit both expression of an extendedspectrum beta-lactamase (ESBL) and halted expression of at least one outer membrane porin (4,5). Porin loss has been clearly shown to enhance levels of antibiotic resistance, and ESBL-positive K. pneumoniae isolates commonly exhibit loss of OmpK35 and OmpK36, which both function in nonspecific transport across the outer membrane (6)(7)(8).…”

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confidence: 99%

Porin Loss Impacts the Host Inflammatory Response to Outer Membrane Vesicles of Klebsiella pneumoniae

Turner

Cahill

Dilello

et al. 2016

Antimicrob Agents Chemother

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Antibiotic-resistant strains of Klebsiella pneumoniae often exhibit porin loss. In this study, we investigated how porin loss impacted the composition of secreted outer membrane vesicles as well as their ability to trigger proinflammatory cytokine secretion by macrophages. We hypothesize that porin loss associated with antibiotic resistance will directly impact both the composition of outer membrane vesicles and their interactions with phagocytic cells. Using clonally related clinical isolates of extended-spectrum beta-lactamase (ESBL)-positive Klebsiella pneumoniae with different patterns of porin expression, we demonstrated that altered expression of OmpK35 and OmpK36 results in broad alterations to the protein profile of secreted vesicles. Additionally, the level of OmpA incorporation was elevated in strains lacking a single porin. Porin loss significantly impacted macrophage inflammatory responses to purified vesicles. Outer membrane vesicles lacking both OmpK35 and OmpK36 elicited significantly lower levels of proinflammatory cytokine secretion than vesicles from strains expressing one or both porins. These data demonstrate that antibiotic resistance-associated porin loss has a broad and significant effect on both the composition of outer membrane vesicles and their interactions with phagocytic cells, which may impact bacterial survival and inflammatory reactions in the host.K lebsiella pneumoniae is a nosocomial pathogen responsible for as many as 20% of all cases of culture-positive blood cultures and bacterial sepsis (1). Alarmingly, up to 50% of these infections are resistant to most current antibiotics (2, 3). The majority of resistant Klebsiella isolates exhibit both expression of an extendedspectrum beta-lactamase (ESBL) and halted expression of at least one outer membrane porin (4, 5). Porin loss has been clearly shown to enhance levels of antibiotic resistance, and ESBL-positive K. pneumoniae isolates commonly exhibit loss of OmpK35 and OmpK36, which both function in nonspecific transport across the outer membrane (6-8).While changes to the porin profile of bacteria are well documented to be associated with enhanced antibiotic resistance (9, 10), the role that these porins play in pathogenesis has not been fully investigated. In vitro experiments using mutants of K. pneumoniae lacking OmpK36 have demonstrated that loss of OmpK36 results in increased phagocytic killing of the bacteria, and in vivo experiments have demonstrated decreased virulence and bacterial survival of strains lacking OmpK36 in a mouse model (11)(12)(13)(14). Data from these studies consistently indicate that loss of OmpK36 results in an increase in antibiotic resistance paired with a decrease in fitness and ability to survive host immune responses. It is unclear how resistant strains of Klebsiella are able to persist in host tissues when porin loss renders the bacteria more susceptible to phagocytic clearance.The capsule is the best understood of the virulence factors of Klebsiella, cloaking the bacterial outer surface from immu...

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“…A clustering analysis based on average nucleotide identity (ANI) (6) revealed that strain DSM 30104 T was most closely related to K. pneumoniae KCTC 2242 (99.03% ANI). Lower ANI values (approximately 98.75% to 98.99%) were found in comparisons to other K. pneumoniae strains sequenced so far (5,7,9,11,13,14). The KCTC 2242 strain was previously reported to produce 2,3-butanediol and to be used in industrial applications as a potential valuable fuel additive (11).…”

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confidence: 97%

“…The (5,7,9,11,13,14). A clustering analysis based on average nucleotide identity (ANI) (6) revealed that strain DSM 30104 T was most closely related to K. pneumoniae KCTC 2242 (99.03% ANI).…”

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confidence: 99%

Draft Genome Sequence of Klebsiella pneumoniae subsp. pneumoniae DSM 30104 ^T

et al. 2012

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Reduced susceptibility to carbapenems in Klebsiella pneumoniae clinical isolates associated with plasmid-mediated β-lactamase production and OmpK36 porin deficiency

Cited by 69 publications

References 33 publications

Klebsiella pneumoniae Major Porins OmpK35 and OmpK36 Allow More Efficient Diffusion of β-Lactams than Their Escherichia coli Homologs OmpF and OmpC

Klebsiella pneumoniae Major Porins OmpK35 and OmpK36 Allow More Efficient Diffusion of β-Lactams than Their Escherichia coli Homologs OmpF and OmpC

Porin Loss Impacts the Host Inflammatory Response to Outer Membrane Vesicles of Klebsiella pneumoniae

Draft Genome Sequence of Klebsiella pneumoniae subsp. pneumoniae DSM 30104 ^T

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Reduced susceptibility to carbapenems in Klebsiella pneumoniae clinical isolates associated with plasmid-mediated β-lactamase production and OmpK36 porin deficiency

Cited by 69 publications

References 33 publications

Klebsiella pneumoniae Major Porins OmpK35 and OmpK36 Allow More Efficient Diffusion of β-Lactams than Their Escherichia coli Homologs OmpF and OmpC

Klebsiella pneumoniae Major Porins OmpK35 and OmpK36 Allow More Efficient Diffusion of β-Lactams than Their Escherichia coli Homologs OmpF and OmpC

Porin Loss Impacts the Host Inflammatory Response to Outer Membrane Vesicles of Klebsiella pneumoniae

Draft Genome Sequence of Klebsiella pneumoniae subsp. pneumoniae DSM 30104 T

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Draft Genome Sequence of Klebsiella pneumoniae subsp. pneumoniae DSM 30104 ^T