scholarly journals Metabolite Transporter PEG344 Is Required for Full Virulence of Hypervirulent Klebsiella pneumoniae Strain hvKP1 after Pulmonary but Not Subcutaneous Challenge

2017 ◽  
Vol 85 (10) ◽  
Author(s):  
Jeffrey Bulger ◽  
Ulrike MacDonald ◽  
Ruth Olson ◽  
Janet Beanan ◽  
Thomas A. Russo
Keyword(s):  
Klebsiella Pneumoniae ◽  
Virulence Factors ◽  
Ex Vivo ◽  
Infection Model ◽  
Virulence Plasmid ◽  
Content Type ◽  
Model Studies ◽  
Life Threatening ◽  
Cd1 Mice

ABSTRACT Hypervirulent Klebsiella pneumoniae (hvKP) is an emerging pathotype that is capable of causing tissue-invasive and organ- and life-threatening infections in healthy individuals from the community. Knowledge on the virulence factors specific to hvKP is limited. In this report, we describe a new factor (PEG344) that increases the virulence of hvKP strain hvKP1. peg-344 is present on the hvKP1 virulence plasmid, is broadly prevalent among hvKP strains, and has increased RNA abundance when grown in human ascites. An isogenic derivative of hvKP1 (hvKP1Δpeg-344) was constructed and compared with its wild-type parent strain in in vitro, ex vivo, and infection model studies. Both survival and competition experiments with outbred CD1 mice demonstrated that PEG344 was required for full virulence after pulmonary challenge but, interestingly, not after subcutaneous challenge. In silico analysis suggested that PEG344 serves as an inner membrane transporter. Compared to hvKP1, a small but significant decrease in the growth/survival of hvKP1Δpeg-344 was observed in human ascites, but resistance to the bactericidal activity of complement was similar. These data suggested that PEG344 may transport an unidentified growth factor present in ascites. The data presented are important since they expand our limited knowledge base on virulence factors unique to hvKP, which is needed to lay the groundwork for translational approaches to prevent or treat these devastating infections.

scholarly journals Pathogenic Leptospira interrogans Exoproteins Are Primarily Involved in Heterotrophic Processes

2015 ◽  
Vol 83 (8) ◽  
pp. 3061-3073 ◽  
Author(s):  
Azad Eshghi ◽  
Elisa Pappalardo ◽  
Svenja Hester ◽  
Benjamin Thomas ◽  
Gabriela Pretre ◽  
...  
Keyword(s):  
Infection Model ◽  
Leptospira Interrogans ◽  
Label Free ◽  
Disease Manifestation ◽  
Pathogenic Leptospira ◽  
Content Type ◽  
Nutrient Sources ◽  
Life Threatening ◽  
Host Mortality

Leptospirosis is a life-threatening and emerging zoonotic disease with a worldwide annual occurrence of more than 1 million cases. Leptospirosis is caused by spirochetes belonging to the genusLeptospira. The mechanisms of disease manifestation in the host remain elusive, and the roles of leptospiral exoproteins in these processes have yet to be determined. Our aim in this study was to assess the composition and quantity of exoproteins of pathogenicLeptospira interrogansand to construe how these proteins contribute to disease pathogenesis. Label-free quantitative mass spectrometry of proteins obtained fromLeptospiraspirochetes culturedin vitrounder conditions mimicking infection identified 325 exoproteins. The majority of these proteins are conserved in the nonpathogenic speciesLeptospira biflexa, and proteins involved in metabolism and energy-generating functions were overrepresented and displayed the highest relative abundance in culture supernatants. Conversely, proteins of unknown function, which represent the majority of pathogen-specific proteins (presumably involved in virulence mechanisms), were underrepresented. Characterization of variousL. interrogansexoprotein mutants in the animal infection model revealed host mortality rates similar to those of hosts infected with wild-typeL. interrogans. Collectively, these results indicate that pathogenicLeptospiraexoproteins primarily function in heterotrophic processes (the processes by which organisms utilize organic substances as nutrient sources) to maintain the saprophytic lifestyle rather than the virulence of the bacteria. The underrepresentation of proteins homologous to known virulence factors, such as toxins and effectors in the exoproteome, also suggests that disease manifesting fromLeptospirainfection is likely caused by a combination of the primary and potentially moonlight functioning of exoproteins.

scholarly journals In VitroandIn VivoActivities of OP0595, a New Diazabicyclooctane, against CTX-M-15-Positive Escherichia coli and KPC-Positive Klebsiella pneumoniae

2016 ◽  
Vol 60 (5) ◽  
pp. 3001-3006 ◽  
Author(s):  
Akihiro Morinaka ◽  
Yuko Tsutsumi ◽  
Keiko Yamada ◽  
Yoshihiro Takayama ◽  
Shiro Sakakibara ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Klebsiella Pneumoniae ◽  
Infection Model ◽  
Gram Negative Bacteria ◽  
Content Type ◽  
Effective Combination ◽  
Time Kill ◽  
Lactamase Inhibitor

ABSTRACTGram-negative bacteria are evolving to produce β-lactamases of increasing diversity that challenge antimicrobial chemotherapy. OP0595 is a new diazabicyclooctane serine β-lactamase inhibitor which acts also as an antibiotic and as a β-lactamase-independent β-lactam “enhancer” againstEnterobacteriaceae. Here we determined the optimal concentration of OP0595 in combination with piperacillin, cefepime, and meropenem, in addition to the antibacterial activity of OP0595 alone and in combination with cefepime, inin vitrotime-kill studies and anin vivoinfection model against five strains of CTX-M-15-positiveEscherichia coliand five strains of KPC-positiveKlebsiella pneumoniae. An OP0595 concentration of 4 μg/ml was found to be sufficient for an effective combination with all three β-lactam agents. In bothin vitrotime-kill studies and anin vivomodel of infection, cefepime-OP0595 showed stronger efficacy than cefepime alone against all β-lactamase-positive strains tested, whereas OP0595 alone showed weaker or no efficacy. Taken together, these data indicate that combinational use of OP0595 and a β-lactam agent is important to exert the antimicrobial functions of OP0595.

scholarly journals Protection against Klebsiella pneumoniae Using Lithium Chloride in an Intragastric Infection Model

2014 ◽  
Vol 59 (3) ◽  
pp. 1525-1533 ◽  
Author(s):  
Nina Tsao ◽  
Chih-Feng Kuo ◽  
Ching-Chen Chiu ◽  
Wei-Chen Lin ◽  
Wan-Hui Huang ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Lithium Chloride ◽  
Blood Levels ◽  
Infection Model ◽  
Dependent Manner ◽  
Toxic Dose ◽  
Content Type ◽  
Bipolar Mood Disorder ◽  
Liver Tissues

ABSTRACTIntragastricKlebsiella pneumoniaeinfections of mice can cause liver abscesses, necrosis of liver tissues, and bacteremia. Lithium chloride, a widely prescribed drug for bipolar mood disorder, has been reported to possess anti-inflammatory properties. Using an intragastric infection model, the effects of LiCl onK. pneumoniaeinfections were examined. Providing mice with drinking water containing LiCl immediately after infection protected them fromK. pneumoniae-induced death and liver injuries, such as necrosis of liver tissues, as well as increasing blood levels of aspartate aminotransferase and alanine aminotransferase, in a dose-dependent manner. LiCl administered as late as 24 h postinfection still provided protection. Monitoring of the LiCl concentrations in the sera ofK. pneumoniae-infected mice showed that approximately 0.33 mM LiCl was the most effective dose for protecting mice against infections, which is lower than the clinically toxic dose of LiCl. Surveys of bacterial counts and cytokine expression levels in LiCl-treated mice revealed that both were effectively inhibited in blood and liver tissues. Usingin vitroassays, we found that LiCl (5 μM to 1 mM) did not directly interfere with the growth ofK. pneumoniaebut madeK. pneumoniaecells lose the mucoid phenotype and become more susceptible to macrophage killing. Furthermore, low doses of LiCl also partially enhanced the bactericidal activity of macrophages. Taken together, these data suggest that LiCl is an alternative therapeutic agent forK. pneumoniae-induced liver infections.

scholarly journals In Vitro-In Vivo Discordance with Humanized Piperacillin-Tazobactam Exposures against Piperacillin-Tazobactam-Resistant/Pan-β-Lactam-Susceptible Klebsiella pneumoniae Strains

2017 ◽  
Vol 61 (7) ◽  
Author(s):  
S. M. Stainton ◽  
M. L. Monogue ◽  
D. P. Nicolau
Keyword(s):  
Klebsiella Pneumoniae ◽  
Lung Infection ◽  
Infection Model ◽  
Clinical Implications ◽  
Content Type ◽  
Murine Lung ◽  
Resistance Profile ◽  
Phenotypic Profile

ABSTRACT Recent findings have identified Klebsiella pneumoniae strains that are pan-β-lactam susceptible (PBL-S) but piperacillin-tazobactam resistant (TZP-R) in vitro. We assessed the efficacy of a humanized exposure of piperacillin-tazobactam (TZP) against 12 TZP-R/PBL-S K. pneumoniae isolates in an immunocompromised murine lung infection model. Discordance between the in vitro resistance profile and the in vivo efficacy of human-simulated TZP exposures against this phenotypic profile was observed. Additional studies are required to define the clinical implications of these TZP-R/PBL-S strains.

scholarly journals In Vitro Discordance with In Vivo Activity: Humanized Exposures of Ceftazidime-Avibactam, Aztreonam, and Tigecycline Alone and in Combination against New Delhi Metallo-β-Lactamase-Producing Klebsiella pneumoniae in a Murine Lung Infection Model

2017 ◽  
Vol 61 (7) ◽  
Author(s):  
M. L. Monogue ◽  
L. M. Abbo ◽  
R. Rosa ◽  
J. F. Camargo ◽  
O. Martinez ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Lung Infection ◽  
Multidrug Resistant ◽  
Infection Model ◽  
New Delhi ◽  
Beta Lactamase ◽  
Bacterial Reduction ◽  
Content Type

ABSTRACT The management of infections with New Delhi metallo-beta-lactamase-1 (NDM)-producing bacteria remains clinically challenging given the multidrug resistant (MDR) phenotype associated with these bacteria. Despite resistance in vitro, ceftazidime-avibactam previously demonstrated in vivo activity against NDM-positive Enterobacteriaceae. Herein, we observed in vitro synergy with ceftazidime-avibactam and aztreonam against an MDR Klebsiella pneumoniae harboring NDM. In vivo, humanized doses of ceftazidime-avibactam monotherapy resulted in >2 log10 CFU bacterial reduction; therefore, no in vivo synergy was observed.

scholarly journals Heterologous Production of 1-Tuberculosinyladenosine in Mycobacterium kansasii Models Pathoevolution towards the Transcellular Lifestyle of Mycobacterium tuberculosis

mBio ◽  
2020 ◽  
Vol 11 (5) ◽  
Author(s):  
Marwan Ghanem ◽  
Jean-Yves Dubé ◽  
Joyce Wang ◽  
Fiona McIntosh ◽  
Daniel Houle ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Virulence Factors ◽  
Ex Vivo ◽  
Nontuberculous Mycobacterium ◽  
Specific Gene ◽  
Bacterial Survival ◽  
Mycobacterium Kansasii ◽  
Content Type ◽  
Lipid Species

ABSTRACT Mycobacterium kansasii is an environmental nontuberculous mycobacterium that causes opportunistic tuberculosis-like disease. It is one of the most closely related species to the Mycobacterium tuberculosis complex. Using M. kansasii as a proxy for the M. kansasii-M. tuberculosis common ancestor, we asked whether introducing the M. tuberculosis-specific gene pair Rv3377c-Rv3378c into M. kansasii affects the course of experimental infection. Expression of these genes resulted in the production of an adenosine-linked lipid species, known as 1-tuberculosinyladenosine (1-TbAd), but did not alter growth in vitro under standard conditions. Production of 1-TbAd enhanced growth of M. kansasii under acidic conditions through a bacterial cell-intrinsic mechanism independent of controlling pH in the bulk extracellular and intracellular spaces. Production of 1-TbAd led to greater burden of M. kansasii in the lungs of C57BL/6 mice during the first 24 h after infection, and ex vivo infections of alveolar macrophages recapitulated this phenotype within the same time frame. However, in long-term infections, production of 1-TbAd resulted in impaired bacterial survival in both C57BL/6 mice and Ccr2−/− mice. We have demonstrated that M. kansasii is a valid surrogate of M. tuberculosis to study virulence factors acquired by the latter organism, yet shown the challenge inherent to studying the complex evolution of mycobacterial pathogenicity with isolated gene complementation. IMPORTANCE This work sheds light on the role of the lipid 1-tuberculosinyladenosine in the evolution of an environmental ancestor to M. tuberculosis. On a larger scale, it reinforces the importance of horizontal gene transfer in bacterial evolution and examines novel models and methods to provide a better understanding of the subtle effects of individual M. tuberculosis-specific virulence factors in infection settings that are relevant to the pathogen.

scholarly journals Virulence Factors Associated with Enterococcus Faecalis Infective Endocarditis: A Mini Review

2017 ◽  
Vol 11 (1) ◽  
pp. 1-11 ◽  
Author(s):  
Kristian T. Madsen ◽  
Marianne N. Skov ◽  
Sabine Gill ◽  
Michael Kemp
Keyword(s):  
Infective Endocarditis ◽  
Enterococcus Faecalis ◽  
Virulence Factors ◽  
Ex Vivo ◽  
Passive Immunization ◽  
Bacterial Attachment ◽  
Factors Associated ◽  
Bacterial Binding ◽  
Life Threatening

Introduction:The enterococci are accountable for up to 20% of all cases of infective endocarditis, withEnterococcus faecalisbeing the primary causative isolate. Infective endocarditis is a life-threatening infection of the endocardium that results in the formation of vegetations. Based on a literature review, this paper provides an overview of the virulence factors associated withE. faecalisinfective endocarditis. Furthermore, it reports the effects of active or passive immunization against some of these involved factors.Individual virulence factors:Nine virulence factors have in particular been associated withE. faecalisinfective endocarditis. Absence of these factors entailed attenuation of strains in both mixed- and mono-bacterial infection endocarditis models as well as inin vitroandex vivoassays when compared to their virulence factor expressing parental strains.Pathogenesis:The virulence factors promote a broad spectrum of events that together allow for disease development and progression. The infection is initiated through bacterial binding to ligands present at the site of infection after which the colonization can be accelerated through inter-bacterial attachment and modulation of the host immune response. The formation and growth of the vegetation provide protection and promote growth. Controlled degeneration of the vegetation appears to increase the likelihood of embolization and dissemination, without exposing protected bacteria.Prophylactic immunization:In most cases, active and passive immunization against associated virulence factors provided partial protection.Future prospects:There is a need for further evaluation of the known virulence factors. Immunization against two or more virulence factors might be an effective prophylactic tool.

scholarly journals Emergence of an NDM-5-Producing Hypervirulent Klebsiella pneumoniae Sequence Type 35 Strain with Chromosomal Integration of an Integrative and Conjugative Element, ICEKp1

2019 ◽  
Vol 64 (1) ◽  
Author(s):  
Zhen Shen ◽  
Qianqian Gao ◽  
Juanxiu Qin ◽  
Yao Liu ◽  
Min Li
Keyword(s):  
Klebsiella Pneumoniae ◽  
Iron Acquisition ◽  
Sequence Type ◽  
Infection Model ◽  
Virulence Plasmid ◽  
Chromosomal Integration ◽  
Content Type ◽  
High Virulence ◽  
Serum Killing ◽  
Integrative And Conjugative Element

ABSTRACT Here, we report an NDM-5-producing sequence type 35 (ST35) hypervirulent Klebsiella pneumoniae strain, isolated from the blood of a male patient. It showed a remarkable resistance to serum killing and neutrophil phagocytosis and high virulence in a mouse peritonitis infection model. Instead of carrying a pLVPK-like virulence plasmid, chromosomal integration of ICEKp1 (∼76 kb) was identified in a specific asparagine-tRNA gene, harboring the iron acquisition system salmochelin genes (iroBCDN), a yersiniabactin gene, and a variant of the rmpA gene.

scholarly journals Immobilization of Antibacterial Dihydropyrrol-2-ones on Functional Polymer Supports To Prevent Bacterial InfectionsIn Vivo

2011 ◽  
Vol 56 (2) ◽  
pp. 1138-1141 ◽  
Author(s):  
Kitty Ka Kit Ho ◽  
Nerida Cole ◽  
Renxun Chen ◽  
Mark D. P. Willcox ◽  
Scott A. Rice ◽  
...  
Keyword(s):  
Staphylococcal Infection ◽  
Infection Model ◽  
Dependent Manner ◽  
Pathogenic Potential ◽  
Antibiotic Resistant ◽  
Content Type ◽  
Polymer Supports ◽  
Wide Range ◽  
Life Threatening

ABSTRACTAntibiotic-resistantStaphylococcus aureusis of great concern, as it causes a wide range of life-threatening infections. The current study demonstrates that dihydropyrrolone (DHP)-coated polyacrylamide substrates are effective in reducing the number of culturable clinical isolates ofS. aureusin vitroin a dose-dependent manner and are able to reduce the pathogenic potential of staphylococcal infection in a subcutaneous infection model. Covalently bound DHPs therefore show great potential for use as an antimicrobial strategy in device-related applications.

scholarly journals Pharmacokinetics-Pharmacodynamics of CB-618 in Combination with Cefepime, Ceftazidime, Ceftolozane, or Meropenem: the Pharmacological Basis for a Stand-Alone β-Lactamase Inhibitor

2017 ◽  
Vol 61 (12) ◽  
Author(s):  
Paul G. Ambrose ◽  
Brian D. VanScoy ◽  
Michael Trang ◽  
Jennifer McCauley-Miller ◽  
Haley Conde ◽  
...  
Keyword(s):  
Infection Model ◽  
Time Curve ◽  
Content Type ◽  
Model Studies ◽  
Time Profiles ◽  
Concentration Time ◽  
The Right ◽  
Dosing Intervals ◽  
Lactamase Inhibitor

ABSTRACT A major challenge in treating patients is the selection of the “right” antibiotic regimen. Given that the optimal β-lactam/β-lactamase inhibitor pair is dependent upon the spectrum of β-lactamase enzymes produced and the frequency of resistance to the β-lactamase inhibitor, it might be useful if a stand-alone were available for the clinician to pair with the “right” β-lactam rather than only in a fixed combination. We describe herein a one-compartment in vitro infection model studies conducted to identify the magnitudes of the pharmacokinetic-pharmacodynamic (PK-PD) index for a β-lactamase inhibitor, CB-618, that would restore the activity of four β-lactam partner agents (cefepime, ceftazidime, ceftolozane, and meropenem) with various doses (1 or 2 g) and dosing intervals (8 or 12 h). The challenge panel included Klebsiella pneumoniae (n = 5), Escherichia coli (n = 2), and Enterobacter cloacae (n = 1) strains, which produced a wide variety of β-lactamase enzymes (AmpC, CTXM-15, KPC-2, KPC-3, FOX-5, OXA-1/30, OXA-48, SHV-1, SHV-11, SHV-27, and TEM-1). Free-drug human concentration-time profiles were simulated for each agent, and specimens were collected for drug concentration and bacterial density determinations. CB-618 restored the activity of each β-lactam partner. The magnitudes of the CB-618 ratio of the area under the concentration-time curve from 0 to 24 h to the MIC (i.e., the AUC/MIC ratio) associated with net bacterial stasis and 1- and 2-log10 CFU/ml reductions from baseline at 24 h were 11.2, 32.9, and 136.3, respectively. These data may provide a PK-PD basis for the development of a stand-alone β-lactamase inhibitor.

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