scholarly journals Sexually Transmitted Neisseria gonorrhoeae Infections—Update on Drug Treatment and Vaccine Development

Medicines ◽  
2021 ◽  
Vol 8 (2) ◽  
pp. 11
Author(s):  
Amber Jefferson ◽  
Amanda Smith ◽  
Pius S. Fasinu ◽  
Dorothea K. Thompson
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Vaccine Development ◽  
Target Identification ◽  
Treatment Options ◽  
New Drugs ◽  
Effective Vaccine ◽  
Sexually Transmitted ◽  
Successful Vaccine ◽  
Future Success ◽  
The Status

Background: Sexually transmitted gonorrhea, caused by the Gram-negative diplococcus Neisseria gonorrhoeae, continues to be a serious global health challenge despite efforts to eradicate it. Multidrug resistance among clinical N. gonorrhoeae isolates has limited treatment options, and attempts to develop vaccines have not been successful. Methods: A search of published literature was conducted, and information extracted to provide an update on the status of therapeutics and vaccine development for gonorrheal infection. Results: Recommended pharmacological treatment for gonorrhea has changed multiple times due to increasing acquisition of resistance to existing antibiotics by N. gonorrhoeae. Only broad-spectrum cephalosporin-based combination therapies are currently recommended for treatment of uncomplicated urogenital and anorectal gonococcal infections. With the reported emergence of ceftriaxone resistance, successful strategies addressing the global burden of gonorrhea must include vaccination. Century-old efforts at developing an effective vaccine against gonorrhea, leading to only four clinical trials, have not yielded any successful vaccine. Conclusions: While it is important to continue to explore new drugs for the treatment of gonorrhea, the historical trend of resistance acquisition suggests that any long-term strategy should include vaccine development. Advanced technologies in proteomics and in silico approaches to vaccine target identification may provide templates for future success.

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 Inhibition of SARS-CoV-2 Replication by a Small Interfering RNA Targeting the Leader Sequence

Viruses ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2030
Author(s):  
Beatrice Tolksdorf ◽  
Chuanxiong Nie ◽  
Daniela Niemeyer ◽  
Viola Röhrs ◽  
Johanna Berg ◽  
...  
Keyword(s):  
Viral Infections ◽  
Vaccine Development ◽  
Treatment Options ◽  
Leader Sequence ◽  
Small Interfering Rnas ◽  
Promising Candidate ◽  
Highly Active ◽  
Successful Vaccine ◽  
Alpha Variant ◽  
New Treatment

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected almost 200 million people worldwide and led to approximately 4 million deaths as of August 2021. Despite successful vaccine development, treatment options are limited. A promising strategy to specifically target viral infections is to suppress viral replication through RNA interference (RNAi). Hence, we designed eight small interfering RNAs (siRNAs) targeting the highly conserved 5’-untranslated region (5’-UTR) of SARS-CoV-2. The most promising candidate identified in initial reporter assays, termed siCoV6, targets the leader sequence of the virus, which is present in the genomic as well as in all subgenomic RNAs. In assays with infectious SARS-CoV-2, it reduced replication by two orders of magnitude and prevented the development of a cytopathic effect. Moreover, it retained its activity against the SARS-CoV-2 alpha variant and has perfect homology against all sequences of the delta variant that were analyzed by bioinformatic means. Interestingly, the siRNA was even highly active in virus replication assays with the SARS-CoV-1 family member. This work thus identified a very potent siRNA with a broad activity against various SARS-CoV viruses that represents a promising candidate for the development of new treatment options.

scholarly journals Multidrug-resistant Neisseria gonorrhoeae with reduced cefotaxime susceptibility is increasingly common in men who have sex with men, Amsterdam, the Netherlands

2009 ◽  
Vol 14 (37) ◽  
Author(s):  
H JC de Vries ◽  
J J van der Helm ◽  
M F Schim van der Loeff ◽  
A P van Dam
Keyword(s):  
The Netherlands ◽  
Neisseria Gonorrhoeae ◽  
Treatment Options ◽  
Multidrug Resistant ◽  
Considerable Proportion ◽  
Third Generation ◽  
Sexually Transmitted ◽  
Sex With Men ◽  
Third Generation Cephalosporins ◽  
Multiple Antibiotics

Antimicrobial resistance is an increasing problem in Neisseria gonorrhoeae (NG) treatment. Presently, third-generation parenteral cephalosporins, like ceftriaxone and cefotaxime, are the first option. Resistance to oral, but not to parenteral, third-generation cephalosporins has been reported previously. We analysed the microbial susceptibility (as minimum inhibitory concentration - MIC) of NG cultures obtained from high-risk visitors of the largest Dutch outpatient clinic for sexually transmitted infections (STI) in Amsterdam, the Netherlands. Among 1,596 visitors, we identified 102 patients with at least one NG isolate with reduced susceptibility to cefotaxime (0.125 μg/ml < MIC ≤ 0.5 μg/ml). The percentage of NG isolates with reduced susceptibility to cefotaxime rose from 4.8% in 2006 to 12.1% in 2008 (chi2 17.5, p<0.001). With multivariate logistic regression, being a man who has sex with men (MSM) was significantly associated with reduced susceptibility to cefotaxime (p<0.001). Compared to susceptible NG isolates, those with decreased susceptiblity to cefotaxime were more often resistant also to penicillin (16.5% vs. 43.3%), tetracycline (21.5% vs. 68.9%) and ciprofloxacin (44.4% vs. 90.0%, all p<0.001). The increased prevalence of NG strains with reduced susceptibility to cefotaxime among MSM may herald resistance to third-generation parenteral cephalosporins. A considerable proportion of these strains show resistance to multiple antibiotics which could limit future NG treatment options.

Vaccines for multidrug resistant Gram negative bacteria: lessons from the past for guiding future success

2020 ◽  
Author(s):  
Mireia López-Siles ◽  
Andrés Corral-Lugo ◽  
Michael J McConnell
Keyword(s):  
Bacterial Infections ◽  
Vaccine Development ◽  
Multidrug Resistant ◽  
Gram Negative Bacteria ◽  
Global Public Health ◽  
Future Directions ◽  
Gram Negative ◽  
The Past ◽  
Successful Vaccine ◽  
Future Success

Abstract Antimicrobial resistance is a major threat to global public health. Vaccination is an effective approach for preventing bacterial infections, however it has not been successfully applied to infections caused by some of the most problematic multidrug resistant pathogens. In this review, the potential for vaccines to contribute to reducing the burden of disease of infections caused by multidrug resistant Gram negative bacteria is presented. Technical, logistical and societal hurdles that have limited successful vaccine development for these infections in the past are identified, and recent advances that can contribute to overcoming these challenges are assessed. A synthesis of vaccine technologies that have been employed in the development of vaccines for key multidrug resistant Gram negative bacteria is included, and emerging technologies that may contribute to future successes are discussed. Finally, a comprehensive review of vaccine development efforts over the last 40 years for three of the most worrisome multidrug resistant Gram negative pathogens, Acinetobacter baumannii, Klebsiella pneumoniae and Pseudomonas aeruginosa is presented, with a focus on recent and ongoing studies. Finally, future directions for the vaccine development field are highlighted.

scholarly journals The status of development of nanoparticle-based swine influenza vaccines: A review

2019 ◽  
Vol 6 (1) ◽  
pp. 6-11
Author(s):  
Uddab Poudel ◽  
Saurav Pantha ◽  
Krishna Kaphle
Keyword(s):  
Bacterial Infections ◽  
Vaccine Development ◽  
Swine Influenza Virus ◽  
Swine Influenza ◽  
Influenza Virus Vaccine ◽  
Viral Disease ◽  
Effective Vaccine ◽  
Prophylactic Measures ◽  
The Status ◽  
Swine Disease

Background Swine are the most important meat animal, famous for white meat, which are prepared as ham, bacon, gammon, sausages and pork. Swine are valuable animals and they are physiologically, immunologically and anatomically similar to humans and their organ can be transplanted to the humans. Due to modernization, the cultural food restriction has lost in the people of urban communities and among the younger generations in Nepal. Gradually changing feeding habit of Nepalese has proven pork to be a useful addition to the food menu. Not only 8.7 lakhs swine in Nepal but the global pig population which occupy 769.05 million are suffering every day from new challenges and threats from very harmful pathogens and diseases like swine dysentery, coccidiosis, swine influenza, etc. Swine influenza is highly contagious rapidly spreading zoonotic viral disease of pigs characterized by febrile respiratory disease often complicated with secondary bacterial infections. Vaccines are only tool for prophylactic measures. There is big challenge for vaccine researchers, manufacturers and scientists for development of effective vaccine regarding swine influenza. Currently available flu vaccines are capable of homologous protection of virus but fail to induce cross protection against frequently evolving heterologous viruses. In this review, we discuss the status of novel nanoparticle-based approach of swine influenza virus vaccine development contributed significantly by Nepalese scientist and the future directions to control this economically important swine disease.

scholarly journals The Impact of Selected Bacterial Sexually Transmitted Diseases on Pregnancy and Female Fertility

2021 ◽  
Vol 22 (4) ◽  
pp. 2170
Author(s):  
Katarzyna Smolarczyk ◽  
Beata Mlynarczyk-Bonikowska ◽  
Ewa Rudnicka ◽  
Dariusz Szukiewicz ◽  
Blazej Meczekalski ◽  
...  
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Treatment Options ◽  
Mycoplasma Genitalium ◽  
Current Treatment ◽  
Female Fertility ◽  
Sexually Transmitted ◽  
Tubal Factor ◽  
Adverse Pregnancy ◽  
New Treatments ◽  
The Impact

Sexually transmitted infections (STIs) caused by Neisseria gonorrhoeae, Chlamydia trachomatis and Mycoplasma genitalium are a common cause of pelvic inflammatory disease (PID) which can lead to tubal factor infertility (TFI). TFI is one of the most common causes of infertility, accounting for 30% of female fertility problems. STIs can also have an impact on pregnancy, leading to adverse pregnancy outcomes. Escalating antibiotic resistance in Neisseria gonorrhoeae and Mycoplasma genitalium represents a significant problem and can be therapeutically challenging. We present a comprehensive review of the current treatment options, as well as the molecular approach to this subject. We have given special attention to molecular epidemiology, molecular diagnostics, current and new treatments, and drug resistance.

scholarly journals Comprehensive Bioinformatic Assessments of the Variability of Neisseria gonorrhoeae Vaccine Candidates

mSphere ◽  
2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Benjamin I. Baarda ◽  
Ryszard A. Zielke ◽  
Alaina K. Holm ◽  
Aleksandra E. Sikora
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Vaccine Development ◽  
Phylogenetic Analyses ◽  
Low Frequency ◽  
Surface Proteins ◽  
Effective Vaccine ◽  
High Morbidity ◽  
Transmitted Infection ◽  
Content Type ◽  
Vaccine Candidates

ABSTRACT A protective vaccine is the only viable way to stop the spread of gonorrhea in the face of rising antibiotic resistance. However, the notorious phase and antigenic variation of Neisseria gonorrhoeae surface proteins remains one of the challenges in vaccine development. To facilitate vaccine advancement efforts, we carried out comprehensive bioinformatic analyses of sequence variation by comparing 34 gonorrhea antigen candidates among >5,000 clinical N. gonorrhoeae isolates deposited in the Neisseria PubMLST database. Eight protein antigens showed exceptional conservation by having a single allele variant distributed in >80% of isolates. An additional 18 vaccine candidates were represented by ≤3 alleles in >50% of N. gonorrhoeae isolates globally. Phylogenetic analyses highlighted closely related antigen variants and additionally showed that AniA and FetB were the closest between N. gonorrhoeae and N. meningitidis. Up to 44% of N. meningitidis alleles for both antigens have premature stop codons, suggesting differential expression. Mapping polymorphisms to the available three-dimensional structures of 12 antigens revealed low-frequency surface polymorphisms. PorB and TbpB possessed numerous high-prevalence polymorphic sites. While TbpA was also highly variable, conserved loops were nonetheless identified. A high degree of sequence conservation, the distribution of a single antigen variant among N. gonorrhoeae strains globally, or low-frequency sequence polymorphisms in surface loops make ACP, AniA, BamA, BamE, MtrE, NspA, NGO0778, NGO1251, NGO1985, OpcA, PldA, Slam2, and ZnuD promising candidates for a gonorrhea vaccine. Finally, the commonly used N. gonorrhoeae FA1090 strain emerges as a vaccine prototype, as it carries antigen sequence types identical to the most broadly distributed antigen variants. IMPORTANCE Neisseria gonorrhoeae, the Gram-negative bacterium responsible for the sexually transmitted infection gonorrhea, is categorized as a high-priority pathogen for research and development efforts. N. gonorrhoeae’s “superbug” status, its high morbidity, and the serious health impact associated with gonorrhea highlight the importance of vaccine development. One of the longstanding barriers to developing an effective vaccine against N. gonorrhoeae is the remarkable variability of surface-exposed antigens. In this report, we addressed this roadblock by applying extensive bioinformatic analyses to 34 gonorrhea antigen candidates among >5,000 clinical N. gonorrhoeae isolates. Our studies are important, as they reveal promising, conserved gonorrhea vaccine candidates and aid structural vaccinology. Moreover, these approaches are broadly applicable to other infectious diseases where surface antigen variability impedes successful vaccine design.

scholarly journals COVID-19: Learning from Lessons To Guide Treatment and Prevention Interventions

mSphere ◽  
2020 ◽  
Vol 5 (3) ◽  
Author(s):  
Chris R. Triggle ◽  
Devendra Bansal ◽  
Elmoubasher Abu Baker Abd Farag ◽  
Hong Ding ◽  
Ali A. Sultan
Keyword(s):  
Vaccine Development ◽  
Effective Vaccine ◽  
Local Health ◽  
Treatment And Prevention ◽  
Health Authorities ◽  
Prevention Interventions ◽  
The Status ◽  
Novel Coronavirus ◽  
Local Health Authorities ◽  
The Impact

ABSTRACT Coronavirus disease 2019 (COVID-19) is caused by the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and first emerged in December 2019 in Wuhan, Hubei province, China. Since then, the virus has rapidly spread to many countries. While the outbreak in China appears to be in decline, the disease has spread across the world, with a daily increase in the number of confirmed cases and infection-related deaths. Here, we highlight (i) the lessons that have been learnt so far and how they will benefit reducing the impact of COVID-19 disease and (ii) an update on the status of drug treatment and vaccine development to prevent COVID-19 and potential future related pandemics. Although the mortality rate is clearly higher than for influenza, the rate does seem to vary from country to country, possibly reflecting differences in how rapidly local health authorities respond to isolate and effectively care for the affected population. Drugs are urgently needed for both prophylaxis and the treatment of severely ill patients; however, no proven effective therapies for SARS-CoV-2 currently exist. A number of drugs that have been approved for other diseases are being tested for the treatment of COVID-19 patients, but there is an absence of data from appropriately designed clinical trials showing that these drugs, either alone or in combination, will prove effective. There is also a global urgency to develop a vaccine against COVID-19, but development and appropriate testing will take at least a year before such a vaccine will be globally available. This review summarizes the lessons learnt so far from the COVID-19 pandemic, examines the evidence regarding the drugs that are being tested for the treatment of COVID19, and describes the progress made in efforts to develop an effective vaccine.

scholarly journals Azithromycin resistant gonococci: a literature review

2020 ◽  
Vol 9 (1) ◽  
Author(s):  
Awoke Derbie ◽  
Daniel Mekonnen ◽  
Yimtubezinash Woldeamanuel ◽  
Tamrat Abebe
Keyword(s):  
Treatment Time ◽  
Efflux Pump ◽  
Treatment Options ◽  
Ribosomal Subunit ◽  
Antimicrobial Treatment ◽  
New Drugs ◽  
Cochrane Library ◽  
Coding Region ◽  
Sexually Transmitted ◽  
Treatment Regimens

Abstract Objective Gonorrhea is the second most common sexually transmitted bacterial infection (STI) next to Chlamydia. Untreated cases could results in major complications like pelvic inflammatory disease (PID), ectopic pregnancy, infertility, miscarriage, fetal death and congenital infections. Gonorrhea has been treated with antibiotics for more than eight decades. However, the emergence and spread of antimicrobial resistance (AMR) in gonococcus seriously compromises the management of the disease. The aim of this review was to describe the current developments in the field of azithromycin resistant gonococci. Methods Literatures published in English in the last 10 years were retrieved from PubMed, SCOPUS, Google scholar, Cochrane library and the Google databases using relevant searching terms. Results Gonococcus is capable of using a number of strategies to confer resistance as the bacterium has an extraordinary capacity to alter its genome. So far the accumulated data on the field showed that the world is heading towards a pandemic of extensively drug-resistant (XDR) gonococcus which is now seems to be evolving into a true “superbug”. Hence, in the near future gonorrhea may become untreatable on the international basis unless new drugs become available. An antibiotic resistance in gonococcus has been noted beginning in 1940s against sulfonamides. Since then, resistance has rapidly emerged to penicillins, tetracyclines, macrolides, fluoroquinolones, and cephalosporins. Currently, in most nations, the injectable extended-spectrum cephalosporin (ESC), i.e. ceftriaxone based therapy is the only remaining option for gonorrhea. Based on the WHO and the US-CDC recommendations, countries are increasingly using a combination of cephalosporin and azithromycin for the treatment of gonorrhoea. Azithromycin revolutionized gonoccocal therapy as it shortened treatment time by more than half from 7 to 14 days and improved patient compliance due to high tissue levels and long half-life. However, constantly emerging reports from different parts of the globe showed that N. gonorrhoeae is developing significant level of resistance against azithromycin, and so far more than 33% level of resistance was reported. Two strategies have been commonly implicated in gonococcal resistance against azithromycin: over expression of an efflux pump (due to mutations at mtrR coding region) and decreased antimicrobial affinity (due to mutations in genes encoding the 23S ribosomal subunit). Conclusions With no alternative antimicrobial treatment options for gonorrhoea and only a few new drugs in the development pipeline, it is necessary to monitor drug resistance and optimize treatment regimens regularly. Moreover, investigations for novel drugs should be wired.

scholarly journals Multiresistant Neisseria gonorrhoeae: a new threat in second decade of the XXI century

2019 ◽  
Vol 209 (2) ◽  
pp. 95-108 ◽  
Author(s):  
Beata Młynarczyk-Bonikowska ◽  
Anna Majewska ◽  
Magdalena Malejczyk ◽  
Grażyna Młynarczyk ◽  
Sławomir Majewski
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Clonal Complex ◽  
Etiologic Agent ◽  
New Drugs ◽  
Sexually Transmitted ◽  
Treatment Regimens ◽  
Resistant Strains ◽  
High Level ◽  
First Time ◽  
Level Resistance

AbstractNeisseria gonorrhoeae is an etiologic agent of gonorrhoea, one of the most common sexually transmitted diseases caused by bacteria. For many years, infections caused by N. gonorrhoeae were considered to be relatively easy to treat; however, resistance has emerged successively to all therapeutic agents used in treatment of the disease, e.g., penicillin, ciprofloxacin or azithromycin. Currently, the global problem is the emergence and a threat of spread of N. gonorrhoeae strains resistant to extended-spectrum cephalosporins (ESC), such as injectable ceftriaxone and oral-used cefixime. Especially, dangerous are multi-resistant strains resistant simultaneously to ESC and azithromycin. Three strains with high-level resistance to azithromycin and resistant to ESC were first time isolated in 2018. Moreover, in 2018, the first ESBL was described in N. gonorrhoeae and that makes the threat of appearing the ESBL mechanism of resistance in N. gonorrhoeae more real, even though the strain was sensitive to ceftriaxone. Molecular typing revealed that variants resistant to ESC occurred also among strains belonging to epidemic clonal complex CC1 (genogroup G1407) distinguished in NG-MAST typing system. The G1407 genogroup, in particular the ST1407 sequence type, is currently dominant in most European countries. The presence of different mechanisms of drug resistance significantly affects clinical practice and force changes in treatment regimens and introduction of new drugs.

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