Gonorrhea

=__**Disease/Drug of interest** : __=

**Motivation and Background** :
Gonorrhea is a sexually transmitted infection (STI) caused by the diplococci, gram-negative bacteria Neisseria gonorrhoeae [10]. Vertical transmission of the infection from mother to child is possible through childbirth and delivery [3]. This disease affects the conjunctival, anorectal, pharyngeal, urogenital, and ovarian areas [12].

Gonorrhea can be asymptomatic in both sexes, hence the strong emphasis on testing in order to maximize disease prevention and management. The most common symptoms include dysuria, urogenital discharge, and in the case of rectal infection, discharge, itching, and difficult or bloody bowel movements [3]. Untreated gonorrhea has different consequences for the male and female sex, though both sexes can become sterile. Women can experience pelvic inflammatory disease (PID) which can result in infertility, ectopic pregnancy, and blocking of the fallopian tubes due to scar tissue formation [3]. In some rare cases, gonorrhea can spread to the blood and joints and may even increase risk of HIV [3]. Newborns that contract gonorrhea from the birth canal can develop blindness due to bilateral conjunctivitis [12].

In the United States, gonorrhea is the second most reported bacterial sexually transmitted infection and is most prevalently found in the south [2]. This disease predominantly affects the African American population and sexually active youths between the ages of fifteen and twenty four [2]. One of the world’s oldest and most prolific infections, gonorrhea has reemerged in recent years as a growing health concern due to gonococcus’ increasing antibiotic resistance to previously used medicines (most notably penicillin, ciprofloxacin, and sulfonilamides) [12]. Treatment heavily depends on the use of cephalosporin medications, Ceftriaxone in particular. The possible evolution of cephalosporin-resistant N. gonorrhoeae into a deadly superbug resistant to all known powerful antibiotics would be disastrous for the state of public health. Unreported statistics and a lack of research done in underrepresented countries suggests that the scientific community lacks a true understanding of the evolutionary capacity of gonococcus in its present state.

[[image:http://www.feinberg.northwestern.edu/gfx/news/NEISSER-gram-stain.gif]]
Figure 3: Light micrograph of Neisseria gonorrhoeae and white cells [9].

1. Ameyama, S.; Onodera, S.; Takahata, M.; Minami, S.; Maki, N.; Endo, K.; Goto, H.; Suzuki, H.; Oishi, Y., Mosaic-like structure of penicillin-binding protein 2 Gene (penA) in clinical isolates of Neisseria gonorrhoeae with reduced susceptibility to cefixime. Antimicrob Agents Chemother 2002,46 (12), 3744-9. 2.Centers for Disease Control and Prevention, 2014 Sexually Transmitted Diseases Surveillance: Gonorrhea. http://www.cdc.gov/std/gonorrhea/stdfact-gonorrhea.htm 3.Centers for Disease Control and Prevention, Gonorrhea: CDC Fact Sheet. http://www.cdc.gov/std/stats14/gonorrhea.htm 4.Clinical Trials, Search for Ceftriaxone, gonorrhea. [] 5.Drugs.com, Ceftriaxone. [] 6.Ito, M.; Deguchi, T.; Mizutani, K. S.; Yasuda, M.; Yokoi, S.; Ito, S.; Takahashi, Y.; Ishihara, S.; Kawamura, Y.; Ezaki, T., Emergence and spread of Neisseria gonorrhoeae clinical isolates harboring mosaic-like structure of penicillin-binding protein 2 in Central Japan. Antimicrob Agents Chemother 2005,49 (1), 137-43. 7. Medline Plus. Ceftriaxone Injection. [] 8. Miller, K., 3EQU: Crystal structure of penicillin-binding protein 2 from Neisseria gonorrhoeae. American Family Physician, 2006; Vol. 73, (2) pp 1779-1784. 9. Northwestern University School of Feinberg Medicine. Professor, Student Identify Alternative DNA Structure for Shape-Shifting Pathogen. http://news.feinberg.northwestern.edu/2009/09/cahoon-seifert/ 10. Powell, A. J.; Tomberg, J.; Deacon, A. M.; Nicholas, R. A.; Davies, C., Crystal structures of penicillin-binding protein 2 from penicillin-susceptible and -resistant strains of Neisseria gonorrhoeae reveal an unexpectedly subtle mechanism for antibiotic resistance. J Biol Chem 2009,284 (2), 1202-12. 11. PubChem. Ceftriaxone. https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5479530&loc=ec_rc [|s]. 12. Unemo, M.; Shafer, W. M., Antimicrobial resistance in Neisseria gonorrhoeae in the 21st century: past, evolution, and future. Clin Microbiol Rev 2014,27 (3), 587-613.
 * References: **

**External links:**
http://www.drugbank.ca/drugs/DB01212 https://www.nlm.nih.gov/medlineplus/ency/article/007267.htm

=__**Target Information** : __= PBPs (Penicilling binding proteins) contribute to cell wall support and the strength of peptidoglycan chain linkages. N. Gonorrhoeae’s immunity can be attributed to m utations in the PBP-2 protein such as reduced porin permeability towards hydrophilic antibiotics (penB mutation), decreased rates of acylation (ponA1 mutation), and reduced rates of PBP-penicillin binding due to changes in the amino acid sequence (penA mutation) [6]. No particular mutation has been identified for resistance to cephalosporin medications, however a mosaic-like structure mutation in PBP-2 genes was reported in Japanese gonorrhea patients with decreased sensitivity to cephalosporin medications [1].

Figure 1: Schematic figure of PBP-2 protein from N. Gonorrhoeae [8]

** Size ** :
PBP-2 has a molecular weight of 121034.38 g/mol [8].

** Location ** :
PBP-2 is anchored to the interior membrane of the cell wall and is involved in forming cell walls during cell replication and division [8].

PBP-2 is one of three penicillin binding proteins found in the bacteria []. This protein is a crucial component in maintaining cell survival due to its involvement in the synthesis of peptidoglycan cross-linkages which help to form, repair, and structure the bacterial cell wall [10].

=__**Drug Information**** : **__= Ceftriaxone, the third-generation cephalosporin, treats disease by causing cell death through the inhibition of penicillin binding protein-2 (PBP-2). By binding its molecular beta-lactam ring to PBPs, Ceftriaxone causes weak, defective cell walls through lesioning, elongation, and general modification to cell permeability [10 ]. Ceftriazone also binds to enzymes involved in cell wall synthesis, specifically carboxypeptidases, transpeptidases, and endopeptidases [11]. The ability of Ceftriaxone to cross the blood-brain barrier makes it valuable in treating CNS infections[11].
 * Schematic figure of drug ** :



Figure 2: Schematic Figure of Ceftriaxone [11]

Ceftriaxone has the molecular formula C18H18N8O7S3 [8].
 * Formula ** :


 * Molecular weight ** :

The molecular weight of this drug is 554.57992 g/mol [8].


 * CAS Number ** :

The CAS Number is 73384-59-5 [8].

This drug is most commonly delivered through an intravenous or intramuscular injection [5]. Ceftriaxone is one of the most successful antibiotics used to treat gonorrhea and can be administered either singularly or in a combination dosage with other prescription medications [12].
 * Delivery method ** :


 * Side effects ** :

Common side effects include fever, chest pain, chills, shortness of breath, dysuria, and tiredness [5]. Rare and serious side effects can include diarrhea, swollen glands, nausea and vomiting, muscle aches, and joint inflammation [5]. Patients with high doses and children are most susceptible to experiencing side effects, however Ceftriaxone is for the most part a well-tolerated drug [5].


 * Other names ** :

Ceftriaxone has a variety of names such as the common brandname Rocephin and Rocephine, Biotrakson, and Ceftriaxonum [8]

Generic ceftriaxone medications are produced by multiple companies. The original is Hoffman-La Roche.
 * Maker or company ** :


 * Is it patented ** ?

As of late, the United States Patent Collection database fails to recognize any Ceftriaxone patents.

Four clinical trials have involved gonorrhea and Ceftriaxone, though only one has been completed and one has been terminated [4].
 * Clinical Trials Info ** :

__** Origin ** : __ Italian pharmacologist Giuseppe Brotzu discovered cephalosporins in 1948 while working with the Sardinian fungus Cephalosporium Acremonium [12]. By isolating chemicals to treat typhoid fever, Brotzu developed a new antimicrobial class which has produced four generations of cephalosporin-medications since.

Alternatives to Ceftriaxone include the third-generation cephalosporins Cefixime and Cefotaxime, as well as the second-generation cephamycin antibiotic Cefoxitin [11].
 * Alternatives to this drug ** :

Ceftriaxone demonstrates success in treating bacterial meningitis, pelvic inflammatory disease (PID), and infections of respiratory, urogenital, and bone nature. Endocarditis, Lyme disease, typhoid fever, and Whipple’s disease are notable diseases which use this drug [7].
 * Other uses ** :