scholarly journals Accessory Gene Regulator-1 Locus Is Essential for Virulence and Pathogenesis ofClostridium difficile

mBio ◽  
2016 ◽  
Vol 7 (4) ◽  
Author(s):  
Charles Darkoh ◽  
Chioma Odo ◽  
Herbert L. DuPont
Keyword(s):  
Health Care ◽  
Therapeutic Target ◽  
Treatment Options ◽  
Toxin Production ◽  
The United States ◽  
Multidrug Resistant ◽  
Accessory Gene ◽  
Ofclostridium Difficile ◽  
Accessory Gene Regulator ◽  
Toxin Regulation

ABSTRACTClostridium difficileinfection (CDI) is responsible for most of the definable cases of antibiotic- and hospital-associated diarrhea worldwide and is a frequent cause of morbidity and mortality in older patients.C. difficile, a multidrug-resistant anaerobic pathogen, causes disease by producing toxins A and B, which are controlled by an accessory gene regulator (Agr) quorum signaling system. SomeC. difficilestrains encode two Agr loci in their genomes, designatedagr1andagr2. Theagr1locus is present in all of theC. difficilestrains sequenced to date, whereas theagr2locus is present in a few strains. The functional roles ofagr1andagr2inC. difficiletoxin regulation and pathogenesis were unknown until now. Using allelic exchange, we deleted components of bothagrloci and examined the mutants for toxin production and virulence. The results showed that theagr1mutant cannot produce toxins A and B; toxin production can be restored by complementation with wild-typeagr1. Furthermore, theagr1mutant is able to colonize but unable to cause disease in a murine CDI model. These findings have profound implications for CDI treatment because we have uncovered a promising therapeutic target for the development of nonantibiotic drugs to treat this life-threatening emerging pathogen by targeting the toxins directly responsible for disease.IMPORTANCEWithin the last decade, the number of cases ofC. difficileinfections has been increasing exponentially in the United States, resulting in about 4.8 billion U.S. dollars in health care costs annually. As a multidrug-resistant, spore-forming, anaerobic pathogen,C. difficileoverpopulates the colon after the gut microbiota has been altered by antibiotic therapy. With increasing resistance to antibiotic treatment ofC. difficileinfections, patients are experiencing higher costs of health care and a lower quality of life as treatment options decrease. During infection,C. difficileproduces toxins A and B, which directly cause disease. As a result, the toxins have become promising nonantibiotic treatment targets. Here, we have identified a pathway responsible for activating the production of the toxins. This important finding opens up a unique therapeutic target for the development of a novel nonantibiotic therapy forC. difficileinfections.

scholarly journals Toxin Synthesis by Clostridium difficile Is Regulated through Quorum Signaling

mBio ◽  
2015 ◽  
Vol 6 (2) ◽  
Author(s):  
Charles Darkoh ◽  
Herbert L. DuPont ◽  
Steven J. Norris ◽  
Heidi B. Kaplan
Keyword(s):  
Clostridium Difficile ◽  
Gut Microbiota ◽  
Antibiotic Therapy ◽  
Molecular Mechanisms ◽  
Public Health Problem ◽  
The United States ◽  
Multidrug Resistant ◽  
Accessory Gene ◽  
Content Type ◽  
Accessory Gene Regulator

ABSTRACTClostridium difficileinfection (CDI) is dramatically increasing as a cause of antibiotic- and hospital-associated diarrhea worldwide. C. difficile, a multidrug-resistant pathogen, flourishes in the colon after the gut microbiota has been altered by antibiotic therapy. Consequently, it produces toxins A and B that directly cause disease. Despite the enormous public health problem posed by this pathogen, the molecular mechanisms that regulate production of the toxins, which are directly responsible for disease, remained largely unknown until now. Here, we show that C. difficile toxin synthesis is regulated by an accessory gene regulator quorum-signaling system, which is mediated through a small (<1,000-Da) thiolactone that can be detected directly in stools of CDI patients. These findings provide direct evidence of the mechanism of regulation of C. difficile toxin synthesis and offer exciting new avenues both for rapid detection of C. difficile infection and development of quorum-signaling-based non-antibiotic therapies to combat this life-threatening emerging pathogen.IMPORTANCEClostridium difficileinfection (CDI) is the most common definable cause of hospital-acquired and antibiotic-associated diarrhea in the United States, with the total cost of treatment estimated between 1 and 4.8 billion U.S. dollars annually. C. difficile, a Gram-positive, spore-forming anaerobe, flourishes in the colon after the gut microbiota has been altered by antibiotic therapy. As a result, there is an urgent need for non-antibiotic CDI treatments that preserve the colonic microbiota. C. difficile produces toxins A and B, which are directly responsible for disease. Here, we report that C. difficile regulates its toxin synthesis by quorum signaling, in which a novel signaling peptide activates transcription of the disease-causing toxin genes. This finding provides new therapeutic targets to be harnessed for novel nonantibiotic therapy for C. difficile infections.

scholarly journals Significant Variability exists in the Toxicity of Global Methicillin-resistant Staphylococcus aureus Lineages.

2021 ◽  
Author(s):  
Maisem Laabei ◽  
Sharon Peacock ◽  
Beth Blane ◽  
Sarah Louise Baines ◽  
Timothy P. Stinear ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Healthcare Setting ◽  
Toxin Production ◽  
Health Concern ◽  
Accessory Gene ◽  
Toxic Activity ◽  
Methicillin Resistant ◽  
Accessory Gene Regulator ◽  
Toxin Regulation ◽  
Reduced Toxicity

Staphylococcus aureus is a major human pathogen where the emergence of antibiotic resistant lineages, such as methicillin-resistant S. aureus (MRSA), is a major health concern. While some MRSA lineages are restricted to the healthcare setting, the epidemiology of MRSA is changing globally, with the rise of specific lineages causing disease in healthy people in the community. In the past two decades, community-associated MRSA (CA-MRSA) has emerged as a clinically important and virulent pathogen associated with serious skin and soft-tissue infections (SSTI). These infections are primarily toxin driven, leading to the suggestion that hyper-virulent lineages/multi-locus sequence types (STs) exist. To examine this, we compared the toxic activity of 475 MRSA isolates representing five major MRSA STs (ST22, ST93, ST8, ST239 and ST36) by employing a monocyte-macrophage THP-1 cell line as a surrogate for measuring gross cytotoxicity. We demonstrate that while certain MRSA STs contain highly toxic isolates, there is such variability within lineages to suggest that this aspect of virulence should not be inferred from the genotype of any given isolate. Furthermore, by interrogating the accessory gene regulator (Agr) sequences in this collection we identified several Agr mutations that were associated with reduced toxicity. Interestingly, the majority of isolates that were attenuated in toxin production contained no mutations in the agr locus, indicating a role of other undefined genes in S. aureus toxin regulation.

scholarly journals Vaccine Protection against Multidrug-Resistant Klebsiella pneumoniae in a Nonhuman Primate Model of Severe Lower Respiratory Tract Infection

mBio ◽  
2019 ◽  
Vol 10 (6) ◽  
Author(s):  
Natalia Malachowa ◽  
Scott D. Kobayashi ◽  
Adeline R. Porter ◽  
Brett Freedman ◽  
Patrick W. Hanley ◽  
...  
Keyword(s):  
United States ◽  
Risk Factors ◽  
Health Care ◽  
Lower Respiratory Tract ◽  
The United States ◽  
Multidrug Resistant ◽  
Sequence Type ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Cynomolgus Macaques

ABSTRACT Klebsiella pneumoniae is a human gut communal organism and notorious opportunistic pathogen. The relative high burden of asymptomatic colonization by K. pneumoniae is often compounded by multidrug resistance—a potential problem for individuals with significant comorbidities or other risk factors for infection. A carbapenem-resistant K. pneumoniae strain classified as multilocus sequence type 258 (ST258) is widespread in the United States and is usually multidrug resistant. Thus, treatment of ST258 infections is often difficult. Inasmuch as new preventive and/or therapeutic measures are needed for treatment of such infections, we developed an ST258 pneumonia model in cynomolgus macaques and tested the ability of an ST258 capsule polysaccharide type 2 (CPS2) vaccine to moderate disease severity. Compared with sham-vaccinated animals, those vaccinated with ST258 CPS2 had significantly less disease as assessed by radiography 24 h after intrabronchial installation of 108 CFU of ST258. All macaques vaccinated with CPS2 ultimately developed ST258-specific antibodies that significantly enhanced serum bactericidal activity and killing of ST258 by macaque neutrophils ex vivo. Consistent with a protective immune response to CPS2, transcripts encoding inflammatory mediators were increased in infected lung tissues obtained from CPS-vaccinated animals compared with control, sham-vaccinated macaques. Taken together, our data provide support for the idea that vaccination with ST258 CPS can be used to prevent or moderate infections caused by ST258. As with studies performed decades earlier, we propose that this prime-boost vaccination approach can be extended to include multiple capsule types. IMPORTANCE Multidrug-resistant bacteria continue to be a major problem worldwide, especially among individuals with significant comorbidities and other risk factors for infection. K. pneumoniae is among the leading causes of health care-associated infections, and the organism is often resistant to multiple classes of antibiotics. A carbapenem-resistant K. pneumoniae strain known as multilocus sequence type 258 (ST258) is the predominant carbapenem-resistant Enterobacteriaceae in the health care setting in the United States. Infections caused by ST258 are often difficult to treat and new prophylactic measures and therapeutic approaches are needed. To that end, we developed a lower respiratory tract infection model in cynomolgus macaques in which to test the ability of ST258 CPS to protect against severe ST258 infection.

Feasibility, Benefits, and Limitations of a Penicillin Allergy Skin Testing Service

2017 ◽  
Vol 51 (6) ◽  
pp. 504-510 ◽  
Author(s):  
Prasanna P. Narayanan ◽  
Meghan N. Jeffres
Keyword(s):  
Health Care ◽  
Clinical Outcomes ◽  
English Language ◽  
Data Extraction ◽  
Financial Burden ◽  
Skin Testing ◽  
The United States ◽  
Multidrug Resistant ◽  
Penicillin Allergy ◽  
Testing Service

Objective: To critically examine the feasibility, benefits, and limitations of an inpatient penicillin skin testing service and how pharmacists can be utilized. Data Sources: A PubMed search was performed from July 2016 through September 2016 using the following search terms: penicillin skin testing, penicillin allergy, β-lactam allergy. Additional references were identified from a review of literature citations. Study Selection and Data Extraction: All English-language studies assessing the use of penicillin skin testing as well as management and clinical outcomes of patients with a β-lactam allergy were evaluated. Data Synthesis: The prevalence of people self-identifying as penicillin allergic ranges from 10% to 20% in the United States. Being improperly labeled as penicillin allergic is associated with higher health care costs, worse clinical outcomes, and an increased prevalence of multidrug-resistant infections. Penicillin skin testing can be a tool used to clarify penicillin allergies and has been demonstrated to be a successful addition to antimicrobial stewardship programs in multiple health care settings. Prior to implementing a penicillin skin testing service, institutions will need to perform a feasibility analysis of who will supply labor and accept the financial burden as well as identify if the positive benefits of a penicillin skin testing service overcome the limitations of this diagnostic test. Conclusion: We conclude that institutions with high percentages of patients receiving non–β-lactams because of penicillin allergy labels would likely benefit the most from a penicillin skin testing service.

scholarly journals Virulence Factors of Clostridioides (Clostridium) difficile Linked to Recurrent Infections

2019 ◽  
Vol 2019 ◽  
pp. 1-7
Author(s):  
Laura Tijerina-Rodríguez ◽  
Licet Villarreal-Treviño ◽  
Rayo Morfín-Otero ◽  
Adrián Camacho-Ortíz ◽  
E. Garza-González
Keyword(s):  
Virulence Factors ◽  
Toxin Production ◽  
Negative Regulator ◽  
Binary Toxin ◽  
Recurrent Infections ◽  
Accessory Gene ◽  
Accessory Gene Regulator ◽  
Cell Internalization ◽  
Adhesion Efficiency ◽  
First Recurrence

From 20 to 30% of Clostridioides (Clostridium) difficile infection (CDI), patients might develop recurrence of the infection (RCDI) and, after the first recurrence, the risk of further episodes increases up to 60%. Several bacterial virulence factors have been associated with RCDI, including the elevated production of toxins A and B, the presence of a binary toxin CDT, and mutations in the negative regulator of toxin expression, tcdC. Additional factors have shown to regulate toxin production and virulence in C. difficile in RCDI, including the accessory-gene regulator agr, which acts as a positive switch for toxin transcription. Furthermore, adhesion and motility-associated factors, such as Cwp84, SlpA, and flagella, have shown to increase the adhesion efficiency to host epithelia, cell internalization, and the formation of biofilm. Finally, biofilm confers to C. difficile protection from antibiotics and acts as a reservoir for spores that allow the persistence of the infection in the host. In this review, we describe the key virulence factors of C. difficile that have been associated with recurrent infections.

scholarly journals Socioeconomic Impact of Irritable Bowel Syndrome in Canada

2001 ◽  
Vol 15 (suppl b) ◽  
pp. 8B-11B ◽  
Author(s):  
Michel Boivin
Keyword(s):  
Health Care ◽  
Irritable Bowel Syndrome ◽  
Health Care Services ◽  
Financial Burden ◽  
Treatment Options ◽  
Indirect Costs ◽  
The United States ◽  
Physician Patient Relationship ◽  
Intangible Costs ◽  
Irritable Bowel

Irritable bowel syndrome (IBS) is the most common functional gastroenterological disorder reported to physicians. In Canada, its prevalence is about 6%. In the United States and the United Kingdom, the prevalence is estimated to be closer to 15%. Patients with IBS tend to make extensive use of health care services, even though a high percentage of them do not seek medical advice. The costs of IBS are a large expenditure of scarce resources. These costs can be divided into several categories: direct, indirect and intangible costs. The direct costs, associated with the diagnosis and treatment, are largely sustained by the health care system. The indirect costs are related to the production losses due to morbidity, and intangible costs are associated with the pain, suffering and alteration in the patient’s quality of life. The condition is a diagnosis of exclusion, and treatment, although beneficial, is rarely curative. The general treatment approach stresses the importance of a good physician-patient relationship. Exploring the nature of the expenses associated with IBS and understanding how treatment options may affect these costs are essential to reducing its financial burden.

scholarly journals Western or Traditional Healers? Understanding Decision Making in the Hmong Population

2016 ◽  
Vol 39 (3) ◽  
pp. 400-415 ◽  
Author(s):  
Maichou Lor ◽  
Phia Xiong ◽  
Linda Park ◽  
Rebecca J. Schwei ◽  
Elizabeth A. Jacobs
Keyword(s):  
Health Care ◽  
Cultural Values ◽  
Treatment Options ◽  
The United States ◽  
Traditional Healers ◽  
Care Utilization ◽  
Structured Interviews ◽  
Host Countries ◽  
Traditional Health ◽  
Health Care Encounters

Research has documented the influence of cultural values, beliefs, and traditional health practices on immigrants’ health care utilization in their host countries. We describe our findings of how Hmong immigrants to the United States make decisions about whether and when to use traditional and/or Western health services. We conducted semi-structured interviews with 11 Hmong adults. We found their decisions depended on whether they classified the illness as spiritual or not and how they evaluated the effectiveness of different treatment options for their illness. Hmong participants’ expectations for effective treatment in traditional or Western health care encounters combined with physical evidence of an illness influenced their decisions and often led them to shift from one type of care to the other. Understanding cultural differences in perceptions of the causes of illnesses and the link between perceived cause and treatment is important to improving care for the Hmong population.

scholarly journals Antibiotic Susceptibility of NDM-Producing Enterobacterales Collected in the United States in 2017 and 2018

2020 ◽  
Vol 64 (9) ◽  
Author(s):  
Joseph D. Lutgring ◽  
Rocío Balbuena ◽  
Natashia Reese ◽  
Sarah E. Gilbert ◽  
Uzma Ansari ◽  
...  
Keyword(s):  
United States ◽  
Antibiotic Susceptibility ◽  
Treatment Options ◽  
The United States ◽  
Multidrug Resistant ◽  
New Delhi ◽  
Drug Resistant ◽  
Carbapenem Resistant ◽  
Extensively Drug Resistant

ABSTRACT The treatment of infections caused by carbapenem-resistant Enterobacterales, especially New Delhi metallo-β-lactamase (NDM)-producing bacteria, is challenging. Although less common in the United States than some other carbapenemase producers, NDM-producing bacteria are a public health threat due to the limited treatment options available. Here, we report on the antibiotic susceptibility of 275 contemporary NDM-producing Enterobacterales collected from 30 U.S. states through the Centers for Disease Control and Prevention’s Antibiotic Resistance Laboratory Network. The aims of the study were to determine the susceptibility of these isolates to 32 currently available antibiotics using reference broth microdilution and to explore the in vitro activity of 3 combination agents that are not yet available. Categorical interpretations were determined using Clinical and Laboratory Standards Institute (CLSI) interpretive criteria. For agents without CLSI criteria, Food and Drug Administration (FDA) interpretive criteria were used. The percentage of susceptible isolates did not exceed 90% for any of the FDA-approved antibiotics tested. The antibiotics with breakpoints that had the highest in vitro activity were tigecycline (86.5% susceptible), eravacycline (66.2% susceptible), and omadacycline (59.6% susceptible); 18.2% of isolates were susceptible to aztreonam. All NDM-producing isolates tested were multidrug resistant, and 116 isolates were extensively drug resistant (42.2%); 207 (75.3%) isolates displayed difficult-to-treat resistance. The difficulty in treating infections caused by NDM-producing Enterobacterales highlights the need for containment and prevention efforts to keep these infections from becoming more common.

scholarly journals Quorum Sensing and Toxin Production in Staphylococcus aureus Osteomyelitis: Pathogenesis and Paradox

Toxins ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 516
Author(s):  
Casey E. Butrico ◽  
James E. Cassat
Keyword(s):  
Staphylococcus Aureus ◽  
Quorum Sensing ◽  
Toxin Production ◽  
High Morbidity ◽  
Invasive Infection ◽  
Accessory Gene ◽  
Accessory Gene Regulator ◽  
Production Factors ◽  
Regulatory Systems ◽  
Skeletal Homeostasis

Staphylococcus aureus is a Gram-positive pathogen capable of infecting nearly every vertebrate organ. Among these tissues, invasive infection of bone (osteomyelitis) is particularly common and induces high morbidity. Treatment of osteomyelitis is notoriously difficult and often requires debridement of diseased bone in conjunction with prolonged antibiotic treatment to resolve infection. During osteomyelitis, S. aureus forms characteristic multicellular microcolonies in distinct niches within bone. Virulence and metabolic responses within these multicellular microcolonies are coordinated, in part, by quorum sensing via the accessory gene regulator (agr) locus, which allows staphylococcal populations to produce toxins and adapt in response to bacterial density. During osteomyelitis, the Agr system significantly contributes to dysregulation of skeletal homeostasis and disease severity but may also paradoxically inhibit persistence in the host. Moreover, the Agr system is subject to complex crosstalk with other S. aureus regulatory systems, including SaeRS and SrrAB, which can significantly impact the progression of osteomyelitis. The objective of this review is to highlight Agr regulation, its implications on toxin production, factors that affect Agr activation, and the potential paradoxical influences of Agr regulation on disease progression during osteomyelitis.

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