scholarly journals Genomic Profiling Reveals Distinct Routes To Complement Resistance in Klebsiella pneumoniae

2020 ◽  
Vol 88 (8) ◽  
Author(s):  
Francesca L. Short ◽  
Gianna Di Sario ◽  
Nathalie T. Reichmann ◽  
Colin Kleanthous ◽  
Julian Parkhill ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Underlying Mechanism ◽  
Genomic Profiling ◽  
Serum Complement ◽  
Complement Components ◽  
Content Type ◽  
Complement Resistance ◽  
Gene Sets ◽  
Capsule Retention ◽  
Selection Of

ABSTRACT The serum complement system is a first line of defense against bacterial invaders. Resistance to killing by serum enhances the capacity of Klebsiella pneumoniae to cause infection, but it is an incompletely understood virulence trait. Identifying and characterizing the factors responsible for preventing activation of, and killing by, serum complement could inform new approaches to treatment of K. pneumoniae infections. Here, we used functional genomic profiling to define the genetic basis of complement resistance in four diverse serum-resistant K. pneumoniae strains (NTUH-K2044, B5055, ATCC 43816, and RH201207), and explored their recognition by key complement components. More than 90 genes contributed to resistance in one or more strains, but only three, rfaH, lpp, and arnD, were common to all four strains. Deletion of the antiterminator rfaH, which controls the expression of capsule and O side chains, resulted in dramatic complement resistance reductions in all strains. The murein lipoprotein gene lpp promoted capsule retention through a mechanism dependent on its C-terminal lysine residue; its deletion led to modest reductions in complement resistance. Binding experiments with the complement components C3b and C5b-9 showed that the underlying mechanism of evasion varied in the four strains: B5055 and NTUH-K2044 appeared to bypass recognition by complement entirely, while ATCC 43816 and RH201207 were able to resist killing despite being associated with substantial levels of C5b-9. All rfaH and lpp mutants bound C3b and C5b-9 in large quantities. Our findings show that, even among this small selection of isolates, K. pneumoniae adopts differing mechanisms and utilizes distinct gene sets to avoid complement attack.

scholarly journals Searching for the Optimal Predictor of Ciprofloxacin Resistance in Klebsiella pneumoniae by UsingIn VitroDynamic Models

2015 ◽  
Vol 60 (3) ◽  
pp. 1208-1215 ◽  
Author(s):  
Elena N. Strukova ◽  
Yury A. Portnoy ◽  
Andrey V. Romanov ◽  
Mikhail V. Edelstein ◽  
Stephen H. Zinner ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Area Under The Curve ◽  
Mutant Selection ◽  
Content Type ◽  
Selection Window ◽  
Mutant Prevention Concentration ◽  
Ciprofloxacin Resistance ◽  
Resistant Mutants ◽  
Time Courses ◽  
Selection Of

There is growing evidence of applicability of the hypothesis of the mutant selection window (MSW), i.e., the range between the MIC and the mutant prevention concentration (MPC), within which the enrichment of resistant mutants is most probable. However, it is not clear if MPC-based pharmacokinetic variables are preferable to the respective MIC-based variables as interstrain predictors of resistance. To examine the predictive power of the ratios of the area under the curve (AUC24) to the MPC and to the MIC, the selection of ciprofloxacin-resistant mutants of threeKlebsiella pneumoniaestrains with different MPC/MIC ratios was studied. Each organism was exposed to twice-daily ciprofloxacin for 3 days at AUC24/MIC ratios that provide peak antibiotic concentrations close to the MIC, between the MIC and the MPC, and above the MPC. ResistantK. pneumoniaemutants were intensively enriched at an AUC24/MIC ratio of 60 to 360 h (AUC24/MPC ratio from 2.5 to 15 h) but not at the lower or higher AUC24/MIC and AUC24/MPC ratios, in accordance with the MSW hypothesis. AUC24/MPC and AUC24/MIC relationships with areas under the time courses of ciprofloxacin-resistantK. pneumoniae(AUBCM) were bell shaped. These relationships predict highly variable “antimutant” AUC24/MPC ratios (20 to 290 h) compared to AUC24/MIC ratios (1,310 to 2,610 h). These findings suggest that the potential of the AUC24/MPC ratio as an interstrain predictor ofK. pneumoniaeresistance is lower than that of the AUC24/MIC ratio.

scholarly journals Survival of Carbapenem-Resistant Klebsiella pneumoniae Sequence Type 258 in Human Blood

2017 ◽  
Vol 61 (4) ◽  
Author(s):  
Frank R. DeLeo ◽  
Scott D. Kobayashi ◽  
Adeline R. Porter ◽  
Brett Freedman ◽  
David W. Dorward ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Human Serum ◽  
Host Defense ◽  
Human Blood ◽  
Bactericidal Activity ◽  
Sequence Type ◽  
Serum Complement ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Normal Human

ABSTRACT Klebsiella pneumoniae is a prominent cause of nosocomial infections worldwide. Bloodstream infections caused by carbapenem-resistant K. pneumoniae, including the epidemic lineage known as multilocus sequence type 258 (ST258), are difficult to treat, and the rate of mortality from such infections is high. Thus, it is imperative that we gain a better understanding of host defense against this pathogen as a step toward developing novel therapies. Here we tested the hypothesis that the resistance of ST258 to bactericidal components of human blood, such as serum complement, is linked to virulence capacity in the context of bacteremia. There was significant variance in the survival of ST258 clinical isolates in heparinized human blood or normal human serum. The rate of survival of ST258 isolates in human blood was, in general, similar to that in normal human serum, suggesting a prominent role for complement (rather than leukocytes) in the healthy host defense against ST258 isolates and related organisms. Indeed, deposition of serum complement—the C5b to C9 (C5b-C9) membrane attack complex—onto the surface of ST258 isolates accompanied serum bactericidal activity. Human serum treated with pharmacological inhibitors of complement, depleted of antibody, or heated at 56°C for 30 min had significantly reduced or absent bactericidal activity. In contrast to heparinized blood from humans, that from BALB/c mice lacked bactericidal activity toward the ST258 isolates tested, but the virulence of these ST258 isolates in a mouse bacteremia model was inexplicably limited. Our data highlight the importance of the complement system in host defense against ST258 bacteremia, and we propose that there is the potential to enhance complement-mediated bactericidal activity using an antibody-based approach.

scholarly journals Phagocytosis of Vibrio cholerae O139 Bengal by Human Polymorphonuclear Leukocytes

1999 ◽  
Vol 6 (2) ◽  
pp. 276-278 ◽  
Author(s):  
M. John Albert ◽  
Firdausi Qadri ◽  
Nurul A. Bhuiyan ◽  
Shaikh M. Ahmad ◽  
M. Ansaruzzaman ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Vibrio Cholerae ◽  
Polymorphonuclear Leukocytes ◽  
Total Resistance ◽  
Serum Complement ◽  
Complement Resistance ◽  
Vibrio Cholerae O139 ◽  
Relative Rarity ◽  
Human Polymorphonuclear Leukocytes

ABSTRACT Capsulated bacteria exhibit serum (complement) resistance and resistance to phagocytosis, which result in disseminated infections.Vibrio cholerae O139 strains possess a thin capsule and have been found to be partially serum resistant in a previous study. In the present study, compared to a standard capsulated Klebsiella pneumoniae strain, which showed total resistance to killing by phagocytosis, V. cholerae O139 strains were shown to be only partially resistant, with most strains showing <40% survival. These findings may explain the relative rarity of V. cholerae O139 bacteremia in cholera caused by this organism.

scholarly journals Proteomic Changes of Klebsiella pneumoniae in Response to Colistin Treatment and crrB Mutation-Mediated Colistin Resistance

2020 ◽  
Vol 64 (6) ◽  
Author(s):  
Lang Sun ◽  
Pernille Kronholm Rasmussen ◽  
Yinlei Bai ◽  
Xiulan Chen ◽  
Tanxi Cai ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Lipid A ◽  
Efflux Pump ◽  
Tca Cycle ◽  
Underlying Mechanism ◽  
Colistin Resistance ◽  
Multidrug Efflux Pump ◽  
Chlorophyll Metabolism ◽  
Content Type ◽  
Proteomic Responses

ABSTRACT Polymyxins are increasingly used as the critical last-resort therapeutic options for multidrug-resistant Gram-negative bacteria. Unfortunately, polymyxin resistance has increased gradually over the past few years. Although studies on polymyxin mechanisms are expanding, systemwide analyses of the underlying mechanism for polymyxin resistance and stress response are still lacking. To understand how Klebsiella pneumoniae adapts to colistin (polymyxin E) pressure, we carried out proteomic analysis of a K. pneumoniae strain cultured with different concentrations of colistin. Our results showed that the proteomic responses to colistin treatment in K. pneumoniae involve several pathways, including (i) gluconeogenesis and the tricarboxylic acid (TCA) cycle, (ii) arginine biosynthesis, (iii) porphyrin and chlorophyll metabolism, and (iv) enterobactin biosynthesis. Interestingly, decreased abundances of class A β-lactamases, including TEM, SHV-11, and SHV-4, were observed in cells treated with colistin. Moreover, we present comprehensive proteome atlases of paired polymyxin-susceptible and -resistant K. pneumoniae strains. The polymyxin-resistant strain Ci, a mutant of K. pneumoniae ATCC BAA 2146, showed a missense mutation in crrB. This crrB mutant, which displayed lipid A modification with 4-amino-4-deoxy-l-arabinose (l-Ara4N) and palmitoylation, showed striking increases in the expression of CrrAB, PmrAB, PhoPQ, ArnBCADT, and PagP. We hypothesize that crrB mutations induce elevated expression of the arnBCADTEF operon and pagP via PmrAB and PhoPQ. Moreover, the multidrug efflux pump KexD, which was induced by crrB mutation, also contributed to colistin resistance. Overall, our results demonstrated proteomic responses to colistin treatment and the mechanism of CrrB-mediated colistin resistance, which may offer valuable information on the management of polymyxin resistance.

scholarly journals Plasmid Dissemination and Selection of a Multidrug-Resistant Klebsiella pneumoniae Strain during Transplant-Associated Antibiotic Therapy

mBio ◽  
2019 ◽  
Vol 10 (5) ◽  
Author(s):  
Sean Conlan ◽  
Anna F. Lau ◽  
Clay Deming ◽  
Christine D. Spalding ◽  
ShihQueen Lee-Lin ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Klebsiella Pneumoniae ◽  
Antibiotic Therapy ◽  
Carbapenem Resistance ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Cell Transplant ◽  
Citrobacter Freundii ◽  
Content Type ◽  
Selection Of

ABSTRACT Antibiotics, which are used both to prevent and to treat infections, are a mainstay therapy for lifesaving procedures such as transplantation. For this reason, and many others, increased antibiotic resistance among human-associated pathogens, such as the carbapenem-resistant Enterobacteriaceae species, is of grave concern. In this study, we report on a hematopoietic stem cell transplant recipient in whom cultures detected the emergence of carbapenem resistance and spread across five strains of bacteria that persisted for over a year. Carbapenem resistance in Citrobacter freundii, Enterobacter cloacae, Klebsiella aerogenes, and Klebsiella pneumoniae was linked to a pair of plasmids, each carrying the Klebsiella pneumoniae carbapenemase gene (blaKPC). Surveillance cultures identified a carbapenem-susceptible strain of Citrobacter freundii that may have become resistant through horizontal gene transfer of these plasmids. Selection of a multidrug-resistant Klebsiella pneumoniae strain was also detected following combination antibiotic therapy. Here we report a plasmid carrying the blaKPC gene with broad host range that poses the additional threat of spreading to endogenous members of the human gut microbiome. IMPORTANCE Antibiotic-resistant bacteria are a serious threat to medically fragile patient populations. The spread of antibiotic resistance through plasmid-mediated mechanisms is of grave concern as it can lead to the conversion of endogenous patient-associated strains to difficult-to-treat pathogens.

scholarly journals Adaptability of Klebsiella pneumoniae 2e, a Newly Isolated 1,3-Propanediol-Producing Strain, to Crude Glycerol as Revealed by Genomic Profiling

2019 ◽  
Vol 85 (10) ◽  
Author(s):  
Jiangshan Ma ◽  
Huan Jiang ◽  
Stanton B. Hector ◽  
Zhihong Xiao ◽  
Jilie Li ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Industrial Application ◽  
Crude Glycerol ◽  
Molecular Mechanisms ◽  
Value Added ◽  
Comparative Genomic ◽  
Genomic Profiling ◽  
Promising Alternative ◽  
Content Type ◽  
Biodiesel Industry

ABSTRACT Crude glycerol is largely generated as the main by-product of the biodiesel industry and is unprofitable for industrial application without costly purification. The direct bioconversion of crude glycerol into 1,3-propanediol (1,3-PDO) by microorganisms is a promising alternative for effective and economic utilization. In this study, Klebsiella pneumoniae 2e was newly isolated for the conversion of crude glycerol into 1,3-PDO. Batch fermentation analysis confirmed that crude glycerol and its main impurities had slight impacts on the growth, key enzyme activity, and 1,3-PDO production of K. pneumoniae 2e. The 1,3-PDO yield from crude glycerol by K. pneumoniae 2e reached 0.64 mol 1,3-PDO/mol glycerol, which was higher than that by most reported 1,3-PDO-producing Klebsiella strains. Genomic profiling revealed that K. pneumoniae 2e possesses 30 genes involved in glycerol anaerobic metabolism and 1,3-PDO biosynthesis. Quantitative real-time PCR analysis of these genes showed that the majority of the genes encoding the key enzymes for glycerol metabolism and 1,3-PDO biosynthesis were significantly upregulated during culture in crude glycerol relative to that in pure glycerol. Further comparative genomic analysis revealed a novel glycerol uptake facilitator protein in K. pneumoniae 2e and a higher number of stress response proteins than in other Klebsiella strains. This work confirms the adaptability of a newly isolated 1,3-PDO-producing strain, K. pneumoniae 2e, to crude glycerol and provides insights into the molecular mechanisms involved in its crude glycerol tolerance, which is valuable for industrial 1,3-PDO production from crude glycerol. IMPORTANCE The rapid development of the biodiesel industry has led to tremendous crude glycerol generation. Due to the presence of complex impurities, crude glycerol has low value for industry without costly purification. Obtaining novel microorganisms capable of direct and efficient bioconversion of crude glycerol to value-added products has great economic potential for industrial application. In this work, we characterized a newly isolated strain, Klebsiella pneumoniae 2e, with the capacity to efficiently produce 1,3-propanediol (1,3-PDO) from crude glycerol and demonstrated its adaptation to crude glycerol. Our work provides insights into the molecular mechanisms of K. pneumoniae 2e adaptation to crude glycerol and the expression patterns of its genes involved in 1,3-PDO biosynthesis, which will contribute to the development of industrial 1,3-PDO production from crude glycerol.

scholarly journals In Vitro Selection of Meropenem Resistance among Ceftazidime-Avibactam-Resistant, Meropenem-Susceptible Klebsiella pneumoniae Isolates with Variant KPC-3 Carbapenemases

2017 ◽  
Vol 61 (5) ◽  
Author(s):  
Ryan K. Shields ◽  
M. Hong Nguyen ◽  
Ellen G. Press ◽  
Liang Chen ◽  
Barry N. Kreiswirth ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
In Vitro Selection ◽  
Carbapenem Resistance ◽  
Wild Type ◽  
Content Type ◽  
Selection Of ◽  
New Mutations

ABSTRACT Ceftazidime-avibactam resistance is mediated by bla KPC-3 mutations, which restore carbapenem susceptibility. We subjected Klebsiella pneumoniae isolates with different bla KPC-3 mutations (n = 5) or wild-type bla KPC-3 (n = 2) to serial passages with meropenem. The meropenem MIC against each isolate increased. Mutations in the ompK36 porin gene evolved in 5 isolates. Among isolates with D179Y substitutions in KPC-3, bla KPC-3 mutations reverted to wild type, were replaced by new mutations, or were retained. Carbapenem treatment of ceftazidime-avibactam-resistant K. pneumoniae infections may select for carbapenem resistance.

scholarly journals Synergistic Activity of Colistin plus Rifampin against Colistin-Resistant KPC-Producing Klebsiella pneumoniae

2013 ◽  
Vol 57 (8) ◽  
pp. 3990-3993 ◽  
Author(s):  
Carlo Tascini ◽  
Enrico Tagliaferri ◽  
Tommaso Giani ◽  
Alessandro Leonildi ◽  
Sarah Flammini ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Multidrug Resistant ◽  
Synergistic Activity ◽  
Content Type ◽  
Extended Spectrum Beta Lactamase ◽  
Carbapenem Resistant ◽  
Resistant Strains ◽  
Antimicrobial Combinations ◽  
Susceptibility Breakpoint ◽  
Selection Of

ABSTRACTInfections caused by carbapenem-resistant KPC-producingKlebsiella pneumoniaeare responsible for high rates of mortality and represent a major therapeutic challenge, especially when the isolates are also resistant to colistin. We used the checkerboard method to evaluate the synergistic activity of 10 antibiotic combinations against 13 colistin-resistant KPC-producingK. pneumoniaeisolates (colistin MIC range of 8 to 128 mg/liter). Colistin plus rifampin was the only combination that demonstrated consistent synergistic bacteriostatic activity against 13/13 strains tested, reducing the colistin MIC below the susceptibility breakpoint (MIC ≤ 2 mg/liter) in 7/13 strains at rifampin concentrations ranging from 4 to 16 mg/liter. Bactericidal synergistic activity was also documented for 8/13 tested strains. Other antimicrobial combinations with carbapenems, gentamicin, and tigecycline showed variously synergistic results. Colistin plus rifampin also exhibited bacteriostatic synergistic activity against 4/4 colistin-susceptible KPC-producingK. pneumoniaeisolates (colistin MIC range of 0.5 to 2 mg/liter) and 4/4 ertapenem-resistant extended-spectrum beta-lactamase (ESBL)-producingK. pneumoniaeisolates (ertapenem MIC range of 16 to 32 mg/liter). Collectively, our data suggest that colistin plus rifampin is the most consistently synergistic combination against KPC-producingK. pneumoniaeisolates, including colistin-resistant strains. Colistin-rifampin combinations may have a role in the treatment of multidrug-resistantK. pneumoniaeand may possibly slow the selection of heteroresistant subpopulations during colistin therapy.

PROMETHEE-based ranking of project managers based on the five personality traits

Kybernetes ◽  
2019 ◽  
Vol 49 (4) ◽  
pp. 1083-1102
Author(s):  
Georgios N. Aretoulis ◽  
Jason Papathanasiou ◽  
Fani Antoniou
Keyword(s):  
Personality Traits ◽  
Questionnaire Survey ◽  
Multicriteria Decision Making ◽  
Project Managers ◽  
Preference Ranking ◽  
Infrastructure Projects ◽  
Public Infrastructure ◽  
Content Type ◽  
The One ◽  
Selection Of

Purpose This paper aims to rank and identify the most efficient project managers (PMs) based on personality traits, using Preference Ranking Organization METHod for Enrichment Evaluations (PROMETHEE) methodology. Design/methodology/approach The proposed methodology relies on the five personality traits. These were used as the selection criteria. A questionnaire survey among 82 experienced engineers was used to estimate the required weights per personality trait. A second two-part questionnaire survey aimed at recording the PMs profile and assess the performance of personality traits per PM. PMs with the most years of experience are selected to be ranked through Visual PROMETHEE. Findings The findings suggest that a competent PM is the one that scores low on the “Neuroticism” trait and high especially on the “Conscientiousness” trait. Research limitations/implications The research applied a psychometric test specifically designed for Greek people. Furthermore, the proposed methodology is based on the personality characteristics to rank the PMs and does not consider the technical skills. Furthermore, the type of project is not considered in the process of ranking PMs. Practical implications The findings could contribute in the selection of the best PM that maximizes the project team’s performance. Social implications Improved project team communication and collaboration leading to improved project performance through better communication and collaboration. This is an additional benefit for the society, especially in the delivery of public infrastructure projects. A lot of public infrastructure projects deviate largely as far as cost and schedule is concerned and this is an additional burden for public and society. Proper project management through efficient PMs would save people’s money and time. Originality/value Identification of the best PMbased on a combination of multicriteria decision-making and psychometric tests, which focus on personality traits.

scholarly journals Characterization of RarA, a Novel AraC Family Multidrug Resistance Regulator in Klebsiella pneumoniae

2012 ◽  
Vol 56 (8) ◽  
pp. 4450-4458 ◽  
Author(s):  
Mark Veleba ◽  
Paul G. Higgins ◽  
Gerardo Gonzalez ◽  
Harald Seifert ◽  
Thamarai Schneiders
Keyword(s):  
Multidrug Resistance ◽  
Klebsiella Pneumoniae ◽  
Efflux Pump ◽  
Content Type ◽  
Resistance Phenotype ◽  
Serratia Proteamaculans ◽  
Virulence Potential ◽  
Article Type ◽  
Acrab Efflux Pump

ABSTRACTTranscriptional regulators, such as SoxS, RamA, MarA, and Rob, which upregulate the AcrAB efflux pump, have been shown to be associated with multidrug resistance in clinically relevant Gram-negative bacteria. In addition to the multidrug resistance phenotype, these regulators have also been shown to play a role in the cellular metabolism and possibly the virulence potential of microbial cells. As such, the increased expression of these proteins is likely to cause pleiotropic phenotypes.Klebsiella pneumoniaeis a major nosocomial pathogen which can express the SoxS, MarA, Rob, and RamA proteins, and the accompanying paper shows that the increased transcription oframAis associated with tigecycline resistance (M. Veleba and T. Schneiders, Antimicrob. Agents Chemother. 56:4466–4467, 2012). Bioinformatic analyses of the availableKlebsiellagenome sequences show that an additional AraC-type regulator is encoded chromosomally. In this work, we characterize this novel AraC-type regulator, hereby called RarA (Regulator of antibiotic resistance A), which is encoded inK. pneumoniae,Enterobactersp. 638,Serratia proteamaculans568, andEnterobacter cloacae. We show that the overexpression ofrarAresults in a multidrug resistance phenotype which requires a functional AcrAB efflux pump but is independent of the other AraC regulators. Quantitative real-time PCR experiments show thatrarA(MGH 78578 KPN_02968) and its neighboring efflux pump operonoqxAB(KPN_02969_02970) are consistently upregulated in clinical isolates collected from various geographical locations (Chile, Turkey, and Germany). Our results suggest thatrarAoverexpression upregulates theoqxABefflux pump. Additionally, it appears thatoqxR, encoding a GntR-type regulator adjacent to theoqxABoperon, is able to downregulate the expression of theoqxABefflux pump, where OqxR complementation resulted in reductions to olaquindox MICs.

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