scholarly journals Repurposed Drugs That Block the Gonococcus-Complement Receptor 3 Interaction Can Prevent and Cure Gonococcal Infection of Primary Human Cervical Epithelial Cells

mBio ◽  
2020 ◽  
Vol 11 (2) ◽  
Author(s):  
Jessica Poole ◽  
Christopher J. Day ◽  
Thomas Haselhorst ◽  
Freda E.-C. Jen ◽  
Victor J. Torres ◽  
...  
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Multidrug Resistant ◽  
Complement Receptor ◽  
Gonococcal Infection ◽  
Domain Interaction ◽  
Lectin Activity ◽  
Content Type ◽  
Cervical Infection ◽  
Binding Epitope ◽  
Complement Receptor 3

ABSTRACT In the absence of a vaccine, multidrug-resistant Neisseria gonorrhoeae has emerged as a major human health threat, and new approaches to treat gonorrhea are urgently needed. N. gonorrhoeae pili are posttranslationally modified by a glycan that terminates in a galactose. The terminal galactose is critical for initial contact with the human cervical mucosa via an interaction with the I-domain of complement receptor 3 (CR3). We have now identified the I-domain galactose-binding epitope and characterized its galactose-specific lectin activity. Using surface plasmon resonance and cellular infection assays, we found that a peptide mimic of this galactose-binding region competitively inhibited the N. gonorrhoeae-CR3 interaction. A compound library was screened for potential drugs that could similarly prohibit the N. gonorrhoeae-CR3 interaction and be repurposed as novel host-targeted therapeutics for multidrug-resistant gonococcal infections in women. Two drugs, methyldopa and carbamazepine, prevented and cured cervical cell infection by multidrug-resistant gonococci by blocking the gonococcal-CR3 I-domain interaction. IMPORTANCE Novel therapies that avert the problem of Neisseria gonorrhoeae with acquired antibiotic resistance are urgently needed. Gonococcal infection of the human cervix is initiated by an interaction between a galactose modification made to its surface appendages, pili, and the I-domain region of (host) complement receptor 3 (CR3). By targeting this crucial gonococcal–I-domain interaction, it may be possible to prevent cervical infection in females. To this end, we identified the I-domain galactose-binding epitope of CR3 and characterized its galactose lectin activity. Moreover, we identified two drugs, carbamazepine and methyldopa, as effective host-targeted therapies for gonorrhea treatment. At doses below those currently used for their respective existing indications, both carbamazepine and methyldopa were more effective than ceftriaxone in curing cervical infection ex vivo. This host-targeted approach would not be subject to N. gonorrhoeae drug resistance mechanisms. Thus, our data suggest a long-term solution to the growing problem of multidrug-resistant N. gonorrhoeae infections.

scholarly journals The Lst Sialyltransferase of Neisseria gonorrhoeae Can Transfer Keto-Deoxyoctanoate as the Terminal Sugar of Lipooligosaccharide: a Glyco-Achilles Heel That Provides a New Strategy for Vaccines to Prevent Gonorrhea

mBio ◽  
2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Freda E.-C. Jen ◽  
Margaret R. Ketterer ◽  
Evgeny A. Semchenko ◽  
Christopher J. Day ◽  
Kate L. Seib ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Neisseria Gonorrhoeae ◽  
Phase Variation ◽  
Multidrug Resistant ◽  
Content Type ◽  
Acetylneuraminic Acid ◽  
New Strategy ◽  
Opsonophagocytic Killing ◽  
Further Development

ABSTRACT The lipooligosaccharide (LOS) of Neisseria gonorrhoeae plays key roles in pathogenesis and is composed of multiple possible glycoforms. These glycoforms are generated by the process of phase variation and by differences in the glycosyltransferase gene content of particular strains. LOS glycoforms of N. gonorrhoeae can be terminated with an N-acetylneuraminic acid (Neu5Ac), which imparts resistance to the bactericidal activity of serum. However, N. gonorrhoeae cannot synthesize the CMP-Neu5Ac required for LOS biosynthesis and must acquire it from the host. In contrast, Neisseria meningitidis can synthesize endogenous CMP-Neu5Ac, the donor molecule for Neu5Ac, which is a component of some meningococcal capsule structures. Both species have an almost identical LOS sialyltransferase, Lst, that transfers Neu5Ac from CMP-Neu5Ac to the terminus of LOS. Lst is homologous to the LsgB sialyltransferase of nontypeable Haemophilus influenzae (NTHi). Studies in NTHi have demonstrated that LsgB can transfer keto-deoxyoctanoate (KDO) from CMP-KDO to the terminus of LOS in place of Neu5Ac. Here, we show that Lst can also transfer KDO to LOS in place of Neu5Ac in both N. gonorrhoeae and N. meningitidis. Consistent with access to the pool of CMP-KDO in the cytoplasm, we present data indicating that Lst is localized in the cytoplasm. Lst has previously been reported to be localized on the outer membrane. We also demonstrate that KDO is expressed as a terminal LOS structure in vivo in samples from infected women and further show that the anti-KDO monoclonal antibody 6E4 can mediate opsonophagocytic killing of N. gonorrhoeae. Taken together, these studies indicate that KDO expressed on gonococcal LOS represents a new antigen for the development of vaccines against gonorrhea. IMPORTANCE The emergence of multidrug-resistant N. gonorrhoeae strains that are resistant to available antimicrobials is a current health emergency, and no vaccine is available to prevent gonococcal infection. Lipooligosaccharide (LOS) is one of the major virulence factors of N. gonorrhoeae. The sialic acid N-acetylneuraminic acid (Neu5Ac) is present as the terminal glycan on LOS in N. gonorrhoeae. In this study, we made an unexpected discovery that KDO can be incorporated as the terminal glycan on LOS of N. gonorrhoeae by the alpha-2,3-sialyltransferase Lst. We showed that N. gonorrhoeae express KDO on LOS in vivo and that the KDO-specific monoclonal antibody 6E4 can direct opsonophagocytic killing of N. gonorrhoeae. These data support further development of KDO-LOS structures as vaccine antigens for the prevention of infection by N. gonorrhoeae.

scholarly journals Trends and Risk Factors for Antimicrobial-Resistant Neisseria gonorrhoeae, Melbourne, Australia, 2007 to 2018

2019 ◽  
Vol 63 (10) ◽  
Author(s):  
Deborah A. Williamson ◽  
Christopher K. Fairley ◽  
Benjamin P. Howden ◽  
Marcus Y. Chen ◽  
Kerrie Stevens ◽  
...  
Keyword(s):  
Risk Factors ◽  
Neisseria Gonorrhoeae ◽  
Laboratory Data ◽  
Northeast Asia ◽  
Public Health Problem ◽  
Multidrug Resistant ◽  
International Travel ◽  
Major Public Health Problem ◽  
Comprehensive Overview ◽  
Content Type

ABSTRACT Antimicrobial resistance (AMR) in Neisseria gonorrhoeae is a major public health problem. Traditionally, AMR surveillance programs for N. gonorrhoeae have focused mainly on laboratory data to describe the prevalence and trends of resistance. However, integrating individual-level risk factors (e.g., sexual orientation or international travel) with laboratory data provides important insights into factors promoting the spread of resistant N. gonorrhoeae. Here, over a 12-year period, we assessed the trends and risk factors for resistant N. gonorrhoeae in individuals attending a large publicly funded sexual health center in Melbourne, Australia. A total of 7,588 N. gonorrhoeae isolates were cultured from 5,593 individuals between 1 January 2007 and 31 December 2018. The proportion of isolates with penicillin resistance decreased from 49.5% in 2007 to 18.3% in 2018 (ptrend < 0.001) and from 63.5% in 2007 to 21.1% in 2018 for ciprofloxacin resistance (ptrend < 0.001). In contrast, the proportion of isolates displaying decreased susceptibility to ceftriaxone increased from 0.5% in 2007 to 2.9% in 2018 (ptrend < 0.001), with a significant increase in low-level azithromycin resistance, from 2.5% in 2012 to 8.2% in 2018 (ptrend < 0.001). Multivariate analysis identified risk factors for multidrug-resistant (MDR) N. gonorrhoeae, namely, female sex and country of birth, with MDR isolates more common in individuals born in northeast Asia, further highlighting the importance of this region and international travel as factors in the cross-border transmission of MDR N. gonorrhoeae. Future surveillance work should incorporate additional epidemiological and genomic data to provide a comprehensive overview of the emergence and spread of resistant N. gonorrhoeae.

Factor H facilitates adherence of Neisseria gonorrhoeae to complement receptor 3 on eukaryotic cells

2010 ◽  
Vol 47 (13) ◽  
pp. 2246-2246
Author(s):  
Sarika Agarwal ◽  
Sanjay Ram ◽  
Jutamas Ngampasutadol ◽  
Sunita Gulati ◽  
Peter F. Zipfel ◽  
...  
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Factor H ◽  
Eukaryotic Cells ◽  
Complement Receptor ◽  
Complement Receptor 3

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.

Neisseria gonorrhoeae use factor H to adhere to complement receptor 3 on eukaryotic cells

2008 ◽  
Vol 45 (16) ◽  
pp. 4169-4170
Author(s):  
Sarika Agarwal ◽  
Sanjay Ram ◽  
Jutamas Ngampasutadol ◽  
Peter Rice
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Factor H ◽  
Eukaryotic Cells ◽  
Complement Receptor ◽  
Complement Receptor 3

scholarly journals Ceftriaxone-Resistant Neisseria gonorrhoeae Isolates (2010 to 2014) in France Characterized by Using Whole-Genome Sequencing

2016 ◽  
Vol 60 (11) ◽  
pp. 6962-6964 ◽  
Author(s):  
Claire de Curraize ◽  
Sylvain Kumanski ◽  
Maïté Micaëlo ◽  
Nelly Fournet ◽  
Guy La Ruche ◽  
...  
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Multidrug Resistant ◽  
Sequence Type ◽  
The Other ◽  
Resistant Isolate ◽  
Whole Genome ◽  
Content Type ◽  
Cephalosporin Resistance

ABSTRACTTwo extended-spectrum cephalosporin-resistantNeisseria gonorrhoeaeisolates were discovered among 6,340 (0.03%) French isolates between 2010 and 2014. One isolate corresponded to the F89 multidrug-resistantN. gonorrhoeaeisolate harboring apenAmosaic; whole-genome sequencing highlighted an additional R251H substitution in theftsXgene recently involved in cephalosporin resistance. The other, ceftriaxone-resistant isolate (MIC, 0.25 mg/liter) harbored the PBP2 pattern XXXVI plus a P551S substitution and belonged to sequence type ST1579 (multilocus sequence typing [MLST]).

scholarly journals Multidrug-Resistant Neisseria gonorrhoeae Isolates from Nanjing, China, Are Sensitive to Killing by a Novel DNA Gyrase Inhibitor, ETX0914 (AZD0914)

2015 ◽  
Vol 60 (1) ◽  
pp. 621-623 ◽  
Author(s):  
Xiao-Hong Su ◽  
Bao-Xi Wang ◽  
Wen-Jing Le ◽  
Yu-Rong Liu ◽  
Chuan Wan ◽  
...  
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Effective Treatment ◽  
Treatment Option ◽  
Dna Gyrase ◽  
Multidrug Resistant ◽  
Effective Treatment Option ◽  
Content Type

ABSTRACTWe tested the activity of ETX0914 against 187Neisseria gonorrhoeaeisolates from men with urethritis in Nanjing, China, in 2013. The MIC50, MIC90, and MIC range for ETX0914 were 0.03 μg/ml, 0.06 μg/ml, and ≤0.002 to 0.125 μg/ml, respectively. All isolates were resistant to ciprofloxacin, and 36.9% (69/187) were resistant to azithromycin. Of the isolates, 46.5% were penicillinase-producingN. gonorrhoeae(PPNG), 36% were tetracycline-resistantN. gonorrhoeae(TRNG), and 13% (24 isolates) had an MIC of 0.125 μg/ml for ceftriaxone. ETX0914 may be an effective treatment option for gonorrhea.

scholarly journals In VitroActivity of Delafloxacin against Clinical Neisseria gonorrhoeae Isolates and Selection of Gonococcal Delafloxacin Resistance

2016 ◽  
Vol 60 (5) ◽  
pp. 3106-3111 ◽  
Author(s):  
Olusegun O. Soge ◽  
Stephen J. Salipante ◽  
David No ◽  
Erin Duffy ◽  
Marilyn C. Roberts
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Spontaneous Mutation ◽  
Efflux Pumps ◽  
Multidrug Resistant ◽  
Cross Resistance ◽  
Content Type ◽  
Resistant Mutants ◽  
Reference Strains ◽  
Selection Of

ABSTRACTWe evaluated thein vitroactivity of delafloxacin against a panel of 117Neisseria gonorrhoeaestrains, including 110 clinical isolates collected from 2012 to 2015 and seven reference strains, compared with the activities of seven antimicrobials currently or previously recommended for treatment of gonorrhea. We examined the potential for delafloxacin to select for resistant mutants in ciprofloxacin-susceptible and ciprofloxacin-resistantN. gonorrhoeae. We characterized mutations in thegyrA,gyrB,parC, andparEgenes and the multidrug-resistant efflux pumps (MtrC-MtrD-MtrE and NorM) by PCR and sequencing and by whole-genome sequencing. The MIC50, MIC90, and MIC ranges of delafloxacin were 0.06 μg/ml, 0.125 μg/ml, and ≤0.001 to 0.25 μg/ml, respectively. The frequency of spontaneous mutation ranged from 10−7to <10−9. The multistep delafloxacin resistance selection of 30 daily passages resulted in stable resistant mutants. There was no obvious cross-resistance to nonfluoroquinolone comparator antimicrobials. A mutant with reduced susceptibility to ciprofloxacin (MIC, 0.25 μg/ml) obtained from the ciprofloxacin-susceptible parental strain had a novel Ser91Tyr alteration in thegyrAgene. We also identified new mutations in thegyrAand/orparCandparEgenes and the multidrug-resistant efflux pumps (MtrC-MtrD-MtrE and NorM) of two mutant strains with elevated delafloxacin MICs of 1 μg/ml. Although delafloxacin exhibited potentin vitroactivity againstN. gonorrhoeaeisolates and reference strains with diverse antimicrobial resistance profiles and demonstrated a low tendency to select for spontaneous mutants, it is important to establish the correlation between these excellentin vitrodata and treatment outcomes through appropriate randomized controlled clinical trials.

scholarly journals Both MisR (CpxR) and MisS (CpxA) Are Required for Neisseria gonorrhoeae Infection in a Murine Model of Lower Genital Tract Infection

2017 ◽  
Vol 85 (9) ◽  
Author(s):  
Dharanesh Gangaiah ◽  
Erica L. Raterman ◽  
Hong Wu ◽  
Kate R. Fortney ◽  
Hongyu Gao ◽  
...  
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Murine Model ◽  
Response Regulator ◽  
Membrane Integrity ◽  
Gonococcal Infection ◽  
Genital Tract Infection ◽  
Content Type ◽  
Constitutive Activation ◽  
Lower Genital Tract Infection

ABSTRACT During infection, Neisseria gonorrhoeae senses and responds to stress; such responses may be modulated by MisRS (NGO0177 and NGO0176), a two-component system that is a homolog of CpxRA. In Escherichia coli, CpxRA senses and responds to envelope stress; CpxA is a sensor kinase/phosphatase for CpxR, a response regulator. When a cpxA mutant is grown in medium containing glucose, CpxR is phosphorylated by acetyl phosphate but cannot be dephosphorylated, resulting in constitutive activation. Kandler and coworkers (J. L. Kandler, C. L. Holley, J. L. Reimche, V. Dhulipala, J. T. Balthazar, A. Muszyński, R. W. Carlson, and W. M. Shafer, Antimicrob Agents Chemother 60:4690–4700, 2016, https://doi.org/10.1128/AAC.00823-16 ) showed that MisR (CpxR) is required for the maintenance of membrane integrity and resistance to antimicrobial peptides, suggesting a role in gonococcal survival in vivo. Here, we evaluated the contributions of MisR and MisS (CpxA) to gonococcal infection in a murine model of cervicovaginal colonization and identified MisR-regulated genes using RNA sequencing (RNA-Seq). The deletion of misR or misS severely reduced the capacity of N. gonorrhoeae to colonize mice or maintain infection over a 7-day period and reduced microbial fitness after exposure to heat shock. Compared to the wild type (WT), the inactivation of misR identified 157 differentially regulated genes, most of which encoded putative envelope proteins. The inactivation of misS identified 17 differentially regulated genes compared to the WT and 139 differentially regulated genes compared to the misR mutant, 111 of which overlapped those differentially expressed in the comparison of the WT versus the misR mutant. These data indicate that an intact MisRS system is required for gonococcal infection of mice. Provided the MisR is constitutively phosphorylated in the misS mutant, the data suggest that controlled but not constitutive activation is required for gonococcal infection in mice.

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