scholarly journals Global Network Analysis of Neisseria gonorrhoeae Identifies Coordination between Pathways, Processes, and Regulators Expressed during Human Infection

mSystems ◽  
2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Ryan McClure ◽  
Ashwini Sunkavalli ◽  
Phillip M. Balzano ◽  
Paola Massari ◽  
Christine Cho ◽  
...  
Keyword(s):  
Network Analysis ◽  
Neisseria Gonorrhoeae ◽  
Treatment Strategies ◽  
High Morbidity ◽  
Gene Coexpression Network ◽  
Transmitted Infection ◽  
Content Type ◽  
Sexually Transmitted ◽  
Gene Coexpression ◽  
New Treatment

ABSTRACT Neisseria gonorrhoeae is a Gram-negative diplococcus that is responsible for the sexually transmitted infection gonorrhea, a high-morbidity disease in the United States and worldwide. Over the past several years, N. gonorrhoeae strains resistant to antibiotics used to treat this infection have begun to emerge across the globe. Thus, new treatment strategies are needed to combat this organism. Here, we utilized N. gonorrhoeae transcriptomic data sets, including those obtained from natural infection of the human genital tract, to infer the first global gene coexpression network of this pathogen. Interrogation of this network revealed genes central to the network that are likely critical for gonococcal growth, metabolism, and virulence, including genes encoding hypothetical proteins expressed during mucosal infection. In addition, network analysis revealed overlap in the response of N. gonorrhoeae to incubation with neutrophils and exposure to hydrogen peroxide stress in vitro. Network analysis also identified new targets of the gonococcal global regulatory protein Fur, while examination of the network neighborhood of genes allowed us to assign additional putative categories to several proteins. Collectively, the characterization of the first gene coexpression network for N. gonorrhoeae described here has revealed new regulatory pathways and new categories for proteins and has shown how processes important to gonococcal infection in both men and women are linked. This information fills a critical gap in our understanding of virulence strategies of this obligate human pathogen and will aid in the development of new treatment strategies for gonorrhea. IMPORTANCE Neisseria gonorrhoeae is the causative agent of the sexually transmitted infection (STI) gonorrhea, a disease with high morbidity worldwide with an estimated 87 million cases annually. Current therapeutic and pharmacologic approaches to treat gonorrhea have been compromised by increased antibiotic resistance worldwide, including to the most recent FDA-approved antibiotic. New treatment strategies are urgently needed to combat this organism. In this study, we used network analysis to interrogate and define the coordination of pathways and processes in N. gonorrhoeae. An analysis of the gonococcal network was also used to assign categories to genes and to expand our understanding of regulatory strategies. Network analysis provides important insights into pathogenic mechanisms of this organism that will guide the design of new strategies for disease treatment.

scholarly journals Trends in antimicrobial susceptibility for azithromycin and ceftriaxone in Neisseria gonorrhoeae isolates in Amsterdam, the Netherlands, between 2012 and 2015

2017 ◽  
Vol 22 (1) ◽  
Author(s):  
Carolien M Wind ◽  
Maarten F Schim van der Loeff ◽  
Alje P van Dam ◽  
Henry JC de Vries ◽  
Jannie J van der Helm
Keyword(s):  
The Netherlands ◽  
Neisseria Gonorrhoeae ◽  
Treatment Strategies ◽  
Sex Partners ◽  
Hiv Status ◽  
Transmitted Infection ◽  
Sexually Transmitted ◽  
New Treatment ◽  
Sex With Men ◽  
Infection Clinic

Resistance of Neisseria gonorrhoeae to azithromycin and ceftriaxone has been increasing in the past years. This is of concern since the combination of these antimicrobials is recommended as the first-line treatment option in most guidelines. To analyse trends in antimicrobial resistance, we retrospectively selected all consultations with a positive N. gonorrhoeae culture at the sexually transmitted infection clinic, Amsterdam, the Netherlands, from January 2012 through September 2015. Minimum inhibitory concentrations (MICs) for azithromycin and ceftriaxone were analysed per year, and determinants associated with decreased susceptibility to azithromycin (MIC > 0.25 mg/L) or ceftriaxone (MIC > 0.032 mg/L) were assessed. Between 2012 and 2015 azithromycin resistance (MIC > 0.5 mg/L) was around 1.2%, the percentage of isolates with intermediate MICs (> 0.25 and ≤ 0.5 mg/L) increased from 3.7% in 2012, to 8.6% in 2015. Determinants associated with decreased azithromycin susceptibility were, for men who have sex with men (MSM), infections diagnosed in the year 2014, two infected sites, and HIV status (HIV; associated with less decreased susceptibility); for heterosexuals this was having ≥ 10 sex partners (in previous six months). Although no ceftriaxone resistance (MIC > 0.125 mg/L) was observed during the study period, the proportion of isolates with decreased ceftriaxone susceptibility increased from 3.6% in 2012, to 8.4% in 2015. Determinants associated with decreased ceftriaxone susceptibility were, for MSM, infections diagnosed in 2014, and pharyngeal infections; and for heterosexuals, infections diagnosed in 2014 or 2015, being of female sex, and having ≥ 10 sex partners. Continued decrease of azithromycin and ceftriaxone susceptibility will threaten future treatment of gonorrhoea. Therefore, new treatment strategies are warranted.

Solithromycin as A Potential Novel Antibiotic Against Neisseria Gonorrhoeae Resistance

2020 ◽  
Author(s):  
Muhammad Habiburrahman ◽  
Vivian  Soetikno ◽  
Wani Riselia Sirait ◽  
Missy Savira
Keyword(s):  
Clinical Trial ◽  
Neisseria Gonorrhoeae ◽  
Wide Distribution ◽  
Phase Iii ◽  
Financial Loss ◽  
Anatomic Site ◽  
Transmitted Infection ◽  
Sexually Transmitted ◽  
Phase Iii Clinical Trials ◽  
New Treatment

Gonorrhea is one of the most often sexually transmitted infection in the world. In 2016, WHO stated the Southeast Asia region as the fourth-highest incidence rate and prevalence of gonorrhea. One of the current problems with gonorrhea is related to its emerging resistance to first-line drugs such as cephalosporins, macrolides, and fluoroquinolones. This resistance has an impact on the difficulty of finding effective antibiotics to eradicate the infection, thus risking financial loss and infertility in sexually active age patients. This literature review will discuss solithromycin, the first fluoroketolide in phase III clinical trial, and show its potential as a new antibiotic against infection with resistant Neisseria gonorrhoeae. Literatures are searched using Pubmed and Google Scholar search engines with keywords: antibiotics, CEM-101, clinical trial, Neisseria gonorrhoeae, new treatment, pharmacology, pharmacokinetics, resistance, safety, and solithromycin. This semisynthetic antibiotic is supported by a different chemical structure from previous macrolides; improving solithromycin becomes more stable and able to bind easier with bacterial ribosomes. Pharmacologically, solithromycin provides an advantage in its high bioavailability, easy oral administration route, wide distribution, metabolism mainly in the liver, but not required dosage adjustments due to hepatic impairment, and a single dosage preparation that can increase patient compliance in healing gonorrhea infections. Also, its lower MIC50 than previous antibiotics makes it well-tolerated, therefore making this antibiotic as a potential recommendation for the management of multi-drug resistant gonorrhea in the future. Solithromycin is not inferior to the standard therapy (ceftriaxone and azithromycin), with 80% vs. 84% gonorrhea eradication rates. Per the anatomic site, the eradication rate is 92% in genital, 94% in the pharynx, and 83% in the rectum. However, special attention needs to be paid to the side effects of the gastrointestinal tract of solithromycin, as observed in phase III clinical trials at a dose of 1000 mg in the form of diarrhea (24%) and nausea (21%).

scholarly journals Transcriptomic Data Sets To Determine Gene Expression Changes Mediated by the Presence of PBT2 in Growth Medium of Multidrug-Resistant Neisseria gonorrhoeae WHO Z

2020 ◽  
Vol 9 (21) ◽  
Author(s):  
Freda E.-C. Jen ◽  
Ibrahim M. El-Deeb ◽  
John M. Atack ◽  
Mark von Itzstein ◽  
Michael P. Jennings
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Transcriptome Sequencing ◽  
Multidrug Resistant ◽  
Data Sets ◽  
Sequencing Data ◽  
Transmitted Infection ◽  
High Coverage ◽  
Content Type ◽  
Sexually Transmitted ◽  
Transcriptomic Data

ABSTRACT Neisseria gonorrhoeae causes the sexually transmitted infection gonorrhea. High-coverage (∼3,300-fold) transcriptome sequencing data have been collected from multidrug-resistant N. gonorrhoeae strain WHO Z grown in the presence and absence of PBT2.

scholarly journals Discovery of a New Neisseria gonorrhoeae Type IV Pilus Assembly Factor, TfpC

mBio ◽  
2020 ◽  
Vol 11 (5) ◽  
Author(s):  
Linda I. Hu ◽  
Shaohui Yin ◽  
Egon A. Ozer ◽  
Lee Sewell ◽  
Saima Rehman ◽  
...  
Keyword(s):  
Cell Surface ◽  
Neisseria Gonorrhoeae ◽  
Bacterial Cell ◽  
Bacterial Species ◽  
Type Iv Pili ◽  
Type Iv Pilus ◽  
Transmitted Infection ◽  
Content Type ◽  
Sexually Transmitted ◽  
Type Iv

ABSTRACT Neisseria gonorrhoeae relies on type IV pili (T4p) to promote colonization of their human host and to cause the sexually transmitted infection gonorrhea. This organelle cycles through a process of extension and retraction back into the bacterial cell. Through a genetic screen, we identified the NGO0783 locus of N. gonorrhoeae strain FA1090 as containing a gene encoding a protein required to stabilize the type IV pilus in its extended, nonretracted conformation. We have named the gene tfpC and the protein TfpC. Deletion of tfpC produces a nonpiliated colony morphology, and immuno-transmission electron microscopy confirms that the pili are lost in the ΔtfpC mutant, although there is some pilin detected near the bacterial cell surface. A copy of the tfpC gene expressed from a lac promoter restores pilus expression and related phenotypes. A ΔtfpC mutant shows reduced levels of pilin protein, but complementation with a tfpC gene restored pilin to normal levels. Bioinformatic searches show that there are orthologues in numerous bacterial species, but not all type IV pilin-expressing bacteria contain orthologous genes. Coevolution and nuclear magnetic resonance (NMR) analysis indicates that TfpC contains an N-terminal transmembrane helix, a substantial extended/unstructured region, and a highly charged C-terminal coiled-coil domain. IMPORTANCE Most bacterial species express one or more extracellular organelles called pili/fimbriae that are required for many properties of each bacterial cell. The Neisseria gonorrhoeae type IV pilus is a major virulence and colonization factor for the sexually transmitted infection gonorrhea. We have discovered a new protein of Neisseria gonorrhoeae called TfpC that is required to maintain type IV pili on the bacterial cell surface. There are similar proteins found in other members of the Neisseria genus and many other bacterial species important for human health.

scholarly journals Challenges and Controversies Concerning Neisseria gonorrhoeae-Neutrophil Interactions in Pathogenesis

mBio ◽  
2021 ◽  
Author(s):  
Alison K. Criss ◽  
Caroline A. Genco ◽  
Scott D. Gray-Owen ◽  
Ann E. Jerse ◽  
H Steven Seifert
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Sexually Transmitted Infection ◽  
Infection Rates ◽  
Transmitted Infection ◽  
Content Type ◽  
Sexually Transmitted

The bacterium Neisseria gonorrhoeae (Ngo) is the main cause of the sexually transmitted infection gonorrhea. The global incidence of 87 million new Ngo infections each year, rising infection rates, and the emergence of Ngo strains that are resistant to all clinically recommended antibiotics have raised the specter of untreatable infections (M.

scholarly journals Men and Women Have Similar Neisseria gonorrhoeae Bacterial Loads: a Comparison of Three Anatomical Sites

2020 ◽  
Vol 58 (11) ◽  
Author(s):  
Brian M. J. W. van der Veer ◽  
Christian J. P. A. Hoebe ◽  
Nicole H. T. M. Dukers-Muijrers ◽  
Lieke B. van Alphen ◽  
Petra F. G. Wolffs
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Bacterial Load ◽  
Large Population ◽  
Transmitted Infection ◽  
Men And Women ◽  
Content Type ◽  
Transmission Potential ◽  
Sexually Transmitted ◽  
Standard Curve ◽  
Sex With Men

ABSTRACT Neisseria gonorrhoeae is a common bacterial sexually transmitted infection (STI). Currently, there are limited data on the bacterial load in both men and women and on both genital and extragenital sites. Therefore, we quantified N. gonorrhoeae bacterial loads in a large population of women, heterosexual men, and men who have sex with men (MSM) at three different anatomical sites. N. gonorrhoeae-positive samples (n = 1265) of STI clinic consultations (n = 944) were tested for N. gonorrhoeae with the Roche Cobas 4800 system, and quantification cycle (Cq) values were used as an inversely proportional measure for N. gonorrhoeae bacterial load after interpolation from a standard curve. Bacterial loads were compared between sample materials and sexes using t tests. The following mean N. gonorrhoeae loads were observed: urine, 4.5 ± 1.0 log10 CFU/ml; vaginal swabs, 4.3 ± 1.1 log10 CFU/ml; anorectal swabs (women), 4.0 ± 1.2 log10 CFU/ml; anorectal swabs (men), 4.5 ± 1.3 log10 CFU/ml; oropharyngeal swabs (women), 2.8 ± 0.9 log10 CFU/ml; and oropharyngeal swabs (men), 3.2 ± 1.0 log10 CFU/ml. Oropharyngeal swabs had a significantly lower N. gonorrhoeae load (P < 0.001) than genital and anorectal samples. Loads did not differ between men and women. This is the first study that determined N. gonorrhoeae load in both women and men at three anatomical sites. The substantial N. gonorrhoeae load at all sample sites suggest that all sites may have transmission potential. However, the oropharyngeal site presents the lowest bacterial load. Men and women have a similar N. gonorrhoeae loads on separate anatomical sites, arguing for similar transmission potential and similar clinical relevance.

scholarly journals MetQ of Neisseria gonorrhoeae Is a Surface-Expressed Antigen That Elicits Bactericidal and Functional Blocking Antibodies

2016 ◽  
Vol 85 (2) ◽  
Author(s):  
Evgeny A. Semchenko ◽  
Christopher J. Day ◽  
Kate L. Seib
Keyword(s):  
Epithelial Cells ◽  
Neisseria Gonorrhoeae ◽  
Transmitted Infection ◽  
Content Type ◽  
Sexually Transmitted ◽  
Bacterial Surface ◽  
Functional Blocking ◽  
Blocking Antibodies ◽  
Candidate Antigen

ABSTRACT Neisseria gonorrhoeae, the causative agent of the sexually transmitted infection (STI) gonorrhea, is a growing public health threat for which a vaccine is urgently needed. We characterized the functional role of the gonococcal MetQ protein, which is the methionine binding component of an ABC transporter system, and assessed its potential as a candidate antigen for inclusion in a gonococcal vaccine. MetQ has been found to be highly conserved in all strains investigated to date, it is localized on the bacterial surface, and it binds l-methionine with a high affinity. MetQ is also involved in gonococcal adherence to cervical epithelial cells. Mutants lacking MetQ have impaired survival in human monocytes, macrophages, and serum. Furthermore, antibodies raised against MetQ are bactericidal and are able to block gonococcal adherence to epithelial cells. These data suggest that MetQ elicits both bactericidal and functional blocking antibodies and is a valid candidate antigen for additional investigation and possible inclusion in a vaccine for prevention of gonorrhea.

scholarly journals High-Level Cefixime- and Ceftriaxone-Resistant Neisseria gonorrhoeae in France: NovelpenAMosaic Allele in a Successful International Clone Causes Treatment Failure

2011 ◽  
Vol 56 (3) ◽  
pp. 1273-1280 ◽  
Author(s):  
Magnus Unemo ◽  
Daniel Golparian ◽  
Robert Nicholas ◽  
Makoto Ohnishi ◽  
Anne Gallay ◽  
...  
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Treatment Failure ◽  
Treatment Strategies ◽  
Public Health Response ◽  
Content Type ◽  
Health Response ◽  
Primary Determinant ◽  
Confirmatory Tests ◽  
New Treatment ◽  
High Level

ABSTRACTRecently, the firstNeisseria gonorrhoeaestrain (H041) highly resistant to the expanded-spectrum cephalosporins (ESCs) ceftriaxone and cefixime, which are the last remaining options for first-line gonorrhea treatment, was isolated in Japan. Here, we confirm and characterize a second strain (F89) with high-level cefixime and ceftriaxone resistance which was isolated in France and most likely caused a treatment failure with cefixime. F89 was examined using six species-confirmatory tests, antibiograms (33 antimicrobials),porBsequencing,N. gonorrhoeaemultiantigen sequence typing (NG-MAST), multilocus sequence typing (MLST), and sequencing of known gonococcal resistance determinants (penA,mtrR,penB,ponA, andpilQ). F89 was assigned to MLST sequence type 1901 (ST1901) and NG-MAST ST1407, which is a successful gonococcal clone that has spread globally. F89 has high-level resistance to cefixime (MIC = 4 μg/ml) and ceftriaxone (MIC = 1 to 2 μg/ml) and resistance to most other antimicrobials examined. A novelpenAmosaic allele (penA-CI), which waspenA-XXXIVwith an additional A501P alteration in penicillin-binding protein 2, was the primary determinant for high-level ESC resistance, as determined by transformation into a set of recipient strains.N. gonorrhoeaeappears to be emerging as a superbug, and in certain circumstances and settings, gonorrhea may become untreatable. Investigations of the biological fitness and enhanced understanding and monitoring of the ESC-resistant clones and their international transmission are required. Enhanced disease control activities, antimicrobial resistance control and surveillance worldwide, and public health response plans for global (and national) perspectives are also crucial. Nevertheless, new treatment strategies and/or drugs and, ideally, a vaccine are essential to develop for efficacious gonorrhea management.

scholarly journals The Iron-Repressed, AraC-Like Regulator MpeR Activates Expression offetAin Neisseria gonorrhoeae

2011 ◽  
Vol 79 (12) ◽  
pp. 4764-4776 ◽  
Author(s):  
Aimee Hollander ◽  
Alexandra Dubon Mercante ◽  
William M. Shafer ◽  
Cynthia Nau Cornelissen
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Iron Transport ◽  
Reproductive Tract ◽  
Treatment Options ◽  
Effective Vaccine ◽  
Transmitted Infection ◽  
Content Type ◽  
Sexually Transmitted ◽  
Treatment And Prevention ◽  
Resistance Rates

ABSTRACTNeisseria gonorrhoeaeis an obligate human pathogen that causes the common sexually transmitted infection gonorrhea. Gonococcal infections cause significant morbidity, particularly among women, as the organism ascends to the upper reproductive tract, resulting in pelvic inflammatory disease, ectopic pregnancy, and infertility. In the last few years, antibiotic resistance rates have risen dramatically, leading to severe restriction of treatment options for gonococcal disease. Gonococcal infections do not elicit protective immunity, nor is there an effective vaccine to prevent the disease. Thus, further understanding of the expression, function, and regulation of surface antigens could lead to better treatment and prevention modalities in the future. In the current study, we determined that an iron-repressed regulator, MpeR, interacted specifically with the DNA sequence upstream offetAand activated FetA expression. Interestingly, MpeR was previously shown to regulate the expression of gonococcal antimicrobial efflux systems. We confirmed that the outer membrane transporter FetA allows gonococcal strain FA1090 to utilize the xenosiderophore ferric enterobactin as an iron source. However, we further demonstrated that FetA has an extended range of substrates that encompasses other catecholate xenosiderophores, including ferric salmochelin and the dimers and trimers of dihydroxybenzoylserine. We demonstrated thatfetAis part of an iron-repressed, MpeR-activated operon which putatively encodes other iron transport proteins. This is the first study to describe a regulatory linkage between antimicrobial efflux and iron transport inN. gonorrhoeae. The regulatory nidus that links these systems, MpeR, is expressed exclusively by pathogenic neisseriae and is therefore expected to be an important virulence factor.

scholarly journals Neisseria gonorrhoeae Metalloprotease NGO1686 Is Required for Full Piliation, and Piliation Is Required for Resistance to H2O2- and Neutrophil-Mediated Killing

mBio ◽  
2013 ◽  
Vol 4 (4) ◽  
Author(s):  
Elizabeth A. Stohl ◽  
Erin M. Dale ◽  
Alison K. Criss ◽  
H. Steven Seifert
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Virulence Factor ◽  
Transmitted Infection ◽  
Content Type ◽  
Sexually Transmitted ◽  
Type Iv ◽  
Specific Pathogen ◽  
Associated Functions ◽  
Host Tissues ◽  
Human Specific

ABSTRACTThe sexually transmitted infection gonorrhea is caused exclusively by the human-specific pathogenNeisseria gonorrhoeae. Type IV pili are an essential virulence factor uniformly expressed on clinical gonococcal isolates and are required for several aspects of gonococcal pathogenesis, including adherence to host tissues, autoagglutination, twitching motility, and the uptake of DNA during transformation. Symptomatic gonococcal infection is characterized by the influx of neutrophils or polymorphonuclear leukocytes (PMNs) to the site of infection. PMNs are a key component of gonococcal pathogenesis, mediating the innate immune response through the use of oxidative and nonoxidative killing mechanisms. The M23B family zinc metallopeptidase NGO1686 is required for gonococci to survive oxidative killing by H2O2- and PMN-mediated killing through unknown mechanisms, but the only known target of NGO1686 is peptidoglycan. We report that the effect of NGO1686 on survival after exposure to H2O2and PMNs is mediated through its role in elaborating pili and that nonpiliated mutants ofN. gonorrhoeaeare less resistant to killing by H2O2, LL-37, and PMNs than the corresponding piliated strains. These findings add to the various virulence-associated functions attributable to gonococcal pili and may explain the selection basis for piliation in clinical isolates ofN. gonorrhoeae.IMPORTANCESuccessful infectious agents need to overcome host defense systems to establish infection. We show that theNeisseriapilus, a major virulence factor of this organism, which causes gonorrhea, helps protect the bacterium from two major killing mechanisms used by the host to combat infections. We also show that to express the pilus, an enzyme needs to partially degrade the cell wall of the bacterium.

Sign in / Sign up

Export Citation Format

Share Document