scholarly journals A Serendipitous Mutation Reveals the Severe Virulence Defect of a Klebsiella pneumoniae fepB Mutant

mSphere ◽  
2017 ◽  
Vol 2 (4) ◽  
Author(s):  
Michelle Palacios ◽  
Christopher A. Broberg ◽  
Kimberly A. Walker ◽  
Virginia L. Miller
Keyword(s):  
Antibiotic Resistance ◽  
Urinary Tract ◽  
Klebsiella Pneumoniae ◽  
Drug Targets ◽  
Carbapenem Resistance ◽  
Content Type ◽  
Hospital Acquired Infections ◽  
Tract Infections ◽  
Hospital Acquired ◽  
Rapid Emergence

ABSTRACT In addition to having a reputation as the causative agent of several types of hospital-acquired infections, Klebsiella pneumoniae has gained widespread attention as a pathogen with a propensity for acquiring antibiotic resistance. It is capable of causing a range of infections, including urinary tract infections, pneumonia, and sepsis. Because of the rapid emergence of carbapenem resistance among Klebsiella strains, there is a dire need for a better understanding of virulence mechanisms and identification of new drug targets. Here, we identify the periplasmic transporter FepB as one such potential target. Klebsiella pneumoniae is considered a significant public health threat because of the emergence of multidrug-resistant strains and the challenge associated with treating life-threatening infections. Capsule, siderophores, and adhesins have been implicated as virulence determinants of K. pneumoniae, yet we lack a clear understanding of how this pathogen causes disease. In a previous screen for virulence genes, we identified a potential new virulence locus and constructed a mutant (smr) with this locus deleted. In this study, we characterize the smr mutant and show that this mutation renders K. pneumoniae avirulent in a pneumonia model of infection. The smr mutant was expected to have a deletion of three genes, but subsequent genome sequencing indicated that a much larger deletion had occurred. Further analysis of the deleted region indicated that the virulence defect of the smr mutant could be attributed to the loss of FepB, a periplasmic protein required for import of the siderophore enterobactin. Interestingly, a ΔfepB mutant was more attenuated than a mutant unable to synthesize enterobactin, suggesting that additional processes are affected. As FepB is highly conserved among the members of the family Enterobacteriaceae, therapeutic targeting of FepB may be useful for the treatment of Klebsiella and other bacterial infections. IMPORTANCE In addition to having a reputation as the causative agent of several types of hospital-acquired infections, Klebsiella pneumoniae has gained widespread attention as a pathogen with a propensity for acquiring antibiotic resistance. It is capable of causing a range of infections, including urinary tract infections, pneumonia, and sepsis. Because of the rapid emergence of carbapenem resistance among Klebsiella strains, there is a dire need for a better understanding of virulence mechanisms and identification of new drug targets. Here, we identify the periplasmic transporter FepB as one such potential target.

scholarly journals Carbapenem-Resistant Klebsiella pneumoniae Urinary Tract Infection following Solid Organ Transplantation

2014 ◽  
Vol 59 (1) ◽  
pp. 553-557 ◽  
Author(s):  
Kyle D. Brizendine ◽  
Sandra S. Richter ◽  
Eric D. Cober ◽  
David van Duin
Keyword(s):  
Urinary Tract ◽  
Klebsiella Pneumoniae ◽  
Solid Organ Transplantation ◽  
Organ Transplant ◽  
Carbapenem Resistance ◽  
First Episode ◽  
Solid Organ ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Tract Infections

ABSTRACTCarbapenem-resistantKlebsiella pneumoniae(CRKP) is an emerging pathogen with a devastating impact on organ transplant recipients (OTRs). Data describing urinary tract infections (UTIs) due to CRKP, compared to extended-spectrum β-lactamase (ESBL)-producing and susceptibleK. pneumoniae, are lacking. We conducted a retrospective cohort study comparing OTRs with a first episode of UTI due to CRKP, ESBL-producingK. pneumoniae, or susceptibleK. pneumoniae. We identified 108 individuals; 22 (20%) had UTIs due to CRKP, 22 (20%) due to ESBL-producingK. pneumoniae, and 64 (60%) due to susceptibleK. pneumoniae. Compared to susceptibleK. pneumoniae(27%), patients with UTIs due to CRKP or ESBL-producingK. pneumoniaewere more likely to have a ≥24-hour stay in the intensive care unit (ICU) before or after development of the UTI (64% and 77%, respectively;P< 0.001). Among 105/108 hospitalized patients (97%), the median lengths of stay prior to UTI with CRKP or ESBL-producingK. pneumoniae(7 and 8 days, respectively) were significantly longer than that for susceptibleK. pneumoniae(1 day;P< 0.001). Clinical failure was observed for 8 patients (36%) with CRKP, 4 (18%) with ESBL-producingK. pneumoniae, and 9 (14%) with susceptibleK. pneumoniae(P= 0.073). Microbiological failure was seen for 10 patients (45%) with CRKP, compared with 2 (9%) with ESBL-producingK. pneumoniaeand 2 (3%) with susceptibleK. pneumoniae(P< 0.001). In multivariable logistic regression analyses, CRKP was associated with greater odds of microbiological failure (versus ESBL-producingK. pneumoniae: odds ratio [OR], 9.36, 95% confidence interval [CI], 1.94 to 72.1; versus susceptibleK. pneumoniae: OR, 31.4, 95% CI, 5.91 to 264). In conclusion, CRKP is associated with ICU admission, long length of stay, and microbiological failure among OTRs with UTIs. Greater numbers are needed to determine risk factors for infection and differences in meaningful endpoints associated with carbapenem resistance.

scholarly journals Identification of Two Regulators of Virulence That Are Conserved inKlebsiella pneumoniaeClassical and Hypervirulent Strains

mBio ◽  
2018 ◽  
Vol 9 (4) ◽  
Author(s):  
Michelle Palacios ◽  
Taryn A. Miner ◽  
Daniel R. Frederick ◽  
Victoria E. Sepulveda ◽  
Joshua D. Quinn ◽  
...  
Keyword(s):  
Gene Expression ◽  
Antibiotic Resistance ◽  
Klebsiella Pneumoniae ◽  
Virulence Factors ◽  
Content Type ◽  
Hospital Acquired Infections ◽  
Capsule Type ◽  
Capsule Production ◽  
Invasive Infections ◽  
Hospital Acquired

ABSTRACTKlebsiella pneumoniaeis widely recognized as a pathogen with a propensity for acquiring antibiotic resistance. It is capable of causing a range of hospital-acquired infections (urinary tract infections [UTI], pneumonia, sepsis) and community-acquired invasive infections. The genetic heterogeneity ofK. pneumoniaeisolates complicates our ability to understand the virulence ofK. pneumoniae. Characterization of virulence factors conserved between strains as well as strain-specific factors will improve our understanding of this important pathogen. The MarR family of regulatory proteins is widely distributed in bacteria and regulates cellular processes such as antibiotic resistance and the expression of virulence factors.Klebsiellaencodes numerous MarR-like proteins, and they likely contribute to the ability ofK. pneumoniaeto respond to and survive under a wide variety of environmental conditions, including those present in the human body. We tested loss-of-function mutations in all themarRhomologues in a murine pneumonia model and found that two (kvrAandkvrB) significantly impacted the virulence of K1 and K2 capsule type hypervirulent (hv) strains and thatkvrAaffected the virulence of a sequence type 258 (ST258) classical strain. In thehvstrains,kvrAandkvrBmutants displayed phenotypes associated with reduced capsule production, mucoviscosity, and transcription fromgalFandmanCpromoters that drive expression of capsule synthesis genes. In contrast,kvrAandkvrBmutants in the ST258 strain had no effect on capsule gene expression or capsule-related phenotypes. Thus, KvrA and KvrB affect virulence in classical andhvstrains but the effect on virulence may not be exclusively due to effects on capsule production.IMPORTANCEIn addition to having a reputation as the causative agent for hospital-acquired infections as well as community-acquired invasive infections,Klebsiella pneumoniaehas gained widespread attention as a pathogen with a propensity for acquiring antibiotic resistance. Due to the rapid emergence of carbapenem resistance amongK. pneumoniaestrains, a better understanding of virulence mechanisms and identification of new potential drug targets are needed. This study identified two novel regulators (KvrA and KvrB) of virulence inK. pneumoniaeand demonstrated that their effect on virulence in invasive strains is likely due in part to effects on capsule production (a major virulence determinant) and hypermucoviscosity. KvrA also impacts the virulence of classical strains but does not appear to affect capsule gene expression in this strain. KvrA and KvrB are conserved amongK. pneumoniaestrains and thus could regulate capsule expression and virulence in diverse strains regardless of capsule type.

scholarly journals Community- and Hospital-Acquired Klebsiella pneumoniae Urinary Tract Infections in Portugal: Virulence and Antibiotic Resistance

2019 ◽  
Vol 7 (5) ◽  
pp. 138 ◽  
Author(s):  
Cátia Caneiras ◽  
Luis Lito ◽  
José Melo-Cristino ◽  
Aida Duarte
Keyword(s):  
Antibiotic Resistance ◽  
Urinary Tract ◽  
Klebsiella Pneumoniae ◽  
Urinary Tract Infections ◽  
Multidrug Resistant ◽  
Hospital Environment ◽  
Virulence Determinants ◽  
Antibiotic Resistance Profile ◽  
Tract Infections ◽  
Hospital Acquired

Klebsiella pneumoniae is a clinically relevant pathogen and a frequent cause of hospital-acquired (HA) and community-acquired (CA) urinary tract infections (UTI). The increased resistance of this pathogen is leading to limited therapeutic options. To investigate the epidemiology, virulence, and antibiotic resistance profile of K. pneumoniae in urinary tract infections, we conducted a multicenter retrospective study for a total of 81 isolates (50 CA-UTI and 31 HA-UTI) in Portugal. The detection and characterization of resistance and virulence determinants were performed by molecular methods (PCR, PCR-based replicon typing, and multilocus sequence typing (MLST)). Out of 50 CA-UTI isolates, six (12.0%) carried β-lactamase enzymes, namely blaTEM-156 (n = 2), blaTEM-24 (n = 1), blaSHV-11 (n = 1), blaSHV-33 (n = 1), and blaCTX-M-15 (n = 1). All HA-UTI were extended-spectrum β-lactamase (ESBL) producers and had a multidrug resistant profile as compared to the CA-UTI isolates, which were mainly resistant to ciprofloxacin, levofloxacin, tigecycline, and fosfomycin. In conclusion, in contrast to community-acquired isolates, there is an overlap between virulence and multidrug resistance for hospital-acquired UTI K. pneumoniae pathogens. The study is the first to report different virulence characteristics for hospital and community K. pneumoniae pathogens, despite the production of β-lactamase and even with the presence of CTX-M-15 ESBL, a successful international ST15 clone, which were identified in both settings. This highlights that a focus on genomic surveillance should remain a priority in the hospital environment.

scholarly journals The Role of ZntA in Klebsiella pneumoniae Zinc Homeostasis

2022 ◽  
Author(s):  
Eve A. Maunders ◽  
Katherine Ganio ◽  
Andrew J. Hayes ◽  
Stephanie L. Neville ◽  
Mark R. Davies ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Urinary Tract ◽  
Klebsiella Pneumoniae ◽  
Zinc Homeostasis ◽  
Healthcare Associated Infections ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Tract Infections ◽  
Healthcare Associated

Klebsiella pneumoniae is a leading cause of healthcare-associated infections, including pneumonia, urinary tract infections, and sepsis. Treatment of K. pneumoniae infections is becoming increasingly challenging due to high levels of antibiotic resistance and the rising prevalence of carbapenem-resistant, extended-spectrum β-lactamases producing strains.

scholarly journals Network Integrative Genomic and Transcriptomic Analysis of Carbapenem-ResistantKlebsiella pneumoniaeStrains Identifies Genes for Antibiotic Resistance and Virulence

mSystems ◽  
2019 ◽  
Vol 4 (4) ◽  
Author(s):  
Muyoung Lee ◽  
Naina Adren Pinto ◽  
Chan Yeong Kim ◽  
Sunmo Yang ◽  
Roshan D’Souza ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Klebsiella Pneumoniae ◽  
Carbapenem Resistance ◽  
Clinical Isolates ◽  
Functional Modules ◽  
Antibiotic Resistant ◽  
Content Type ◽  
Functional Association ◽  
Carbapenem Resistant ◽  
Tract Infections

ABSTRACTGlobal increases in the use of carbapenems have resulted in several strains of Gram-negative bacteria acquiring carbapenem resistance, thereby limiting treatment options.Klebsiella pneumoniaeis a common carbapenem-resistant pathogenic bacterium that is widely studied to identify novel antibiotic resistance mechanisms and drug targets. Antibiotic-resistant clinical isolates generally harbor many genetic alterations, and the identification of responsible mutations would provide insights into the molecular mechanisms of antibiotic resistance. We propose a method to prioritize mutated genes responsible for antibiotic resistance on the basis of expression changes in their local subnetworks, hypothesizing that mutated genes that show significant expression changes among the corresponding functionally associated genes are more likely to be involved in the carbapenem resistance. For network-based gene prioritization, we developed KlebNet (www.inetbio.org/klebnet), a genome-scale cofunctional network ofK. pneumoniaegenes. Using KlebNet, we reconstructed the functional modules for carbapenem resistance and virulence and identified the functional association between antibiotic resistance and virulence. Using complementation assays with the top candidate genes, we were able to validate a novel gene that negatively regulated carbapenem resistance and four novel genes that positively regulated virulence inGalleria mellonellalarvae. Therefore, our study demonstrated the feasibility of network-based identification of genes required for antibiotic resistance and virulence of human-pathogenic bacteria.IMPORTANCEKlebsiella pneumoniaeis a major bacterial pathogen that causes pneumonia and urinary tract infections in human.K. pneumoniaeinfections are treated with carbapenem, but carbapenem-resistantK. pneumoniaehas been spreading worldwide. We are able to identify antimicrobial-resistant genes among mutated genes of the antibiotic-resistant clinical isolates. However, they usually harbor many mutated genes, including those that cause weak or neutral functional effects. Therefore, we need to prioritize the mutated genes to identify the more likely candidates for the follow-up functional analysis. For this study, we present a functional network ofK. pneumoniaegenes and propose a network-based method of prioritizing the mutated genes of the resistant clinical isolates. We also reconstructed the network-based functional modules for carbapenem resistance and virulence and retrieved the functional association between antibiotic resistance and virulence. This study demonstrated the feasibility of network-based analysis of clinical genomics data for the study ofK. pneumoniaeinfection.

scholarly journals The Metal Ion-Dependent Adhesion Site Motif of the Enterococcus faecalis EbpA Pilin Mediates Pilus Function in Catheter-Associated Urinary Tract Infection

mBio ◽  
2012 ◽  
Vol 3 (4) ◽  
Author(s):  
Hailyn V. Nielsen ◽  
Pascale S. Guiton ◽  
Kimberly A. Kline ◽  
Gary C. Port ◽  
Jerome S. Pinkner ◽  
...  
Keyword(s):  
Urinary Tract ◽  
Enterococcus Faecalis ◽  
Molecular Basis ◽  
Metal Ion ◽  
Content Type ◽  
Hospital Acquired Infections ◽  
Tract Infections ◽  
Hospital Acquired ◽  
Adhesion Site

ABSTRACT Though the bacterial opportunist Enterococcus faecalis causes a myriad of hospital-acquired infections (HAIs), including catheter-associated urinary tract infections (CAUTIs), little is known about the virulence mechanisms that it employs. However, the endocarditis- and biofilm-associated pilus (Ebp), a member of the sortase-assembled pilus family, was shown to play a role in a mouse model of E. faecalis ascending UTI. The Ebp pilus comprises the major EbpC shaft subunit and the EbpA and EbpB minor subunits. We investigated the biogenesis and function of Ebp pili in an experimental model of CAUTI using a panel of chromosomal pilin deletion mutants. A nonpiliated pilus knockout mutant (EbpABC− strain) was severely attenuated compared to its isogenic parent OG1RF in experimental CAUTI. In contrast, a nonpiliated ebpC deletion mutant (EbpC− strain) behaved similarly to OG1RF in vivo because it expressed EbpA and EbpB. Deletion of the minor pilin gene ebpA or ebpB perturbed pilus biogenesis and led to defects in experimental CAUTI. We discovered that the function of Ebp pili in vivo depended on a predicted metal ion-dependent adhesion site (MIDAS) motif in EbpA’s von Willebrand factor A domain, a common protein domain among the tip subunits of sortase-assembled pili. Thus, this study identified the Ebp pilus as a virulence factor in E. faecalis CAUTI and also defined the molecular basis of this function, critical knowledge for the rational development of targeted therapeutics. IMPORTANCE Catheter-associated urinary tract infections (CAUTIs), one of the most common hospital-acquired infections (HAIs), present considerable treatment challenges for physicians. Inherently resistant to several classes of antibiotics and with a propensity to acquire vancomycin resistance, enterococci are particularly worrisome etiologic agents of CAUTI. A detailed understanding of the molecular basis of Enterococcus faecalis pathogenesis in CAUTI is necessary for the development of preventative and therapeutic strategies. Our results elucidated the importance of the E. faecalis Ebp pilus and its subunits for enterococcal virulence in a mouse model of CAUTI. We further showed that the metal ion-dependent adhesion site (MIDAS) motif in EbpA is necessary for Ebp function in vivo. As this motif occurs in other sortase-assembled pili, our results have implications for the molecular basis of virulence not only in E. faecalis CAUTI but also in additional infections caused by enterococci and other Gram-positive pathogens.

scholarly journals Complete Genome Sequence of Klebsiella pneumoniae Phage Sweeny

2019 ◽  
Vol 8 (39) ◽  
Author(s):  
Nicholas Martinez ◽  
Eric Williams ◽  
Heather Newkirk ◽  
Mei Liu ◽  
Jason J. Gill ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Complete Genome Sequence ◽  
Protein Level ◽  
Multidrug Resistant ◽  
Content Type ◽  
Hospital Acquired Infections ◽  
Multidrug Resistant Bacterium ◽  
Protein Encoding ◽  
Hospital Acquired ◽  
Encoding Genes

Klebsiella pneumoniae is a multidrug-resistant bacterium causing many severe hospital-acquired infections. Here, we describe siphophage Sweeny that infects K. pneumoniae. Of its 78 predicted protein-encoding genes, a functional assignment was given to 36 of them. Sweeny is most closely related to T1-like phages at the protein level.

scholarly journals Complete Genome Sequence of Klebsiella pneumoniae Myophage Mulock

2019 ◽  
Vol 8 (46) ◽  
Author(s):  
Lorna Min ◽  
Lauren Lessor ◽  
Chandler O’Leary ◽  
Rachele Bonasera ◽  
Jason Gill ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Genome Sequence ◽  
Complete Genome Sequence ◽  
Complete Genome ◽  
Opportunistic Pathogen ◽  
Phage Lambda ◽  
Content Type ◽  
Hospital Acquired Infections ◽  
Genes Encoding ◽  
Hospital Acquired

Klebsiella pneumoniae is an opportunistic pathogen associated with hospital-acquired infections. This report describes the complete genome of the K. pneumoniae myophage Mulock, which appears to be a temperate myophage distantly related to other Klebsiella myophages in morphogenesis genes and is partially syntenic with the canonical Escherichia phage lambda in genes encoding lambda-like functions.

scholarly journals Characterization and Plasmid Profile of Resistant Klebsiella pneumoniae Isolates in Patients with Urinary Tract Infection in Nasarawa State, Nigeria

2020 ◽  
Vol 8 (1) ◽  
pp. 21-28
Author(s):  
Olukayode Olugbenga Orole ◽  
Naja’atu Shehu Hadi
Keyword(s):  
Antibiotic Resistance ◽  
Urinary Tract ◽  
Klebsiella Pneumoniae ◽  
Healthcare Providers ◽  
Early Morning ◽  
Plasmid Profile ◽  
Resistance Pattern ◽  
Dna Profile ◽  
Beta Lactamases ◽  
Tract Infections

Klebsiella pneumoniae has been identified as an urgent threat to human health based on its increasing antimicrobial resistance to the beta-lactamases and Carbapenemases. The pathogen has become a threat to both patients and healthcare providers as its incidence is on the increase, becoming a major global healthcare issue. The study was aimed at characterizing and determining the plasmid profile of resistant Klebsiella pneumoniae isolates from urinary tract of patients at Dalhatu Araf Specialist Hospital Lafia, Nasarawa State, Nigeria. Early morning mid-stream urine samples were collected from patients with urinary tract infections between April and May, 2019 and Klebsiella pneumoniae characterized on the basis of its antibiotic resistance pattern, and the plasmid DNA profile determined. Thirty-eight strains of resistant Klebsiella pneumoniae were obtained of which 33 showed resistance to more than three antibiotics. About 51.1% of the isolates were resistant to Tetracycline, while the isolates were least resistant to Azithromycin and Cefotaxime (30.3%) respectively. Klebsiella pneumoniae isolates showed 32 different resistance patterns, 24 of the strains had the capacity to produce Extended Spectrum Beta-lactamases enzymes: CTX-M 24(72.7%), SHV 19(57.6%) and TEM 16(48.5%) respectively. All the resistant Klebsiella pneumoniae isolated had the same plasmid size of 48.5 kilobases and only 1 plasmid each though they all obtained a multiple antibiotic resistance (MAR) index > 0.2. The study concluded that Klebsiella pneumoniae harbours genes which confer antibiotic resistance on the isolates. The study exposes further the challenge of antibiotic resistance and need for concerted effort at stopping the challenge of drug resistance. Int. J. Appl. Sci. Biotechnol. Vol 8(1): 21-28

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