Melioidosis

=Disease/Drug of interest: MELIODIDOSIS/ CO-TRIMOXAZOLE =

Motivation and Background:
Melioidosis is an infectious disease caused by gram-negative bacterium, that is widespread in Southeast Asia and northern Australia, Burkholderia pseudomallei. It is most commonly known as the Whitmore’s disease and can be commonly be mistaken as other infectious diseases due to its wide range of symptoms. Symptoms may include those ranging to localized, pulmonary, bloodstream, and disseminated infections. Even worse, the time between the exposure span from one day to many years, so there is no indication of when the transmission happened [1]. Melioidosis is susceptible at high endemic regions especially in Thailand, where it is one of the major health problems.



Because the bacterium Burkholderia pseudomalleus is resistant to many antimicrobial drugs, many drugs will decline after some use, so the doses taken must be taken into consideration. For instance, the bacterium is resistant to penicillin and other widely known treatment. To treat Melioidosis there are two phases: acute phase and the eradication phase [3]. This write up will focus on one of the drug administered during the eradication phase: Co- trimoxazole or otherwise known as trimethoprim/sulfamethoxazole [4].

[1.] Centers for Disease Control and Prevention. CDC 24/7: Saving Lives, Protecting People. http://www.cdc.gov/melioidosis/signs-symptoms.html. (accessed Feb 07, 2016). [2.] Cheng, A.; Currie, B., Melioidosis: Epidemiology, Pathophysiology, and Management. Clinical Microbiology Review 2005, 18 (2), 383-416. [3.] Crowe, A.; McMahon, N.; Currie, B. J.; Baird, R. W., Current antimicrobial susceptibility of first-episode melioidosis Burkholderia pseudomallei isolates from the Northern Territory, Australia. Int J Antimicrob Agents 2014, 44 (2), 160-162. [4.] Dance, D., Treatment and prophylaxis of melioidosis. Int J Antimicrob Agents 2014, 43 (4), 310-8. [5.]Biological Magnetic Resonance Data Bank. BMRB Featured System: Dihydrofolate Reductase. http://www.bmrb.wisc.edu/featuredSys/dhfr/dhfr1.shtml. (accessed Feb 07, 2016). [6.] Global RPh. The Clinician’s Ultimate Reference. http://www.globalrph.com/bactrim_dilution.htm. (accessed Feb 07, 2016). [7.] PhosphoSite Plus. Protein Page: DHFR (human). http://www.phosphosite.org/proteinAction. action?id=2888800. (accessed Feb 07, 2016). [8.] Luk, L.; Loveridge, E.; Allemann, R.;, Protein motions and dynamic effects in enzyme catalysis. Royal Society of Chemistry 2015, 17 (36), 30817 - 30827. [9.] Chetchotisakd, P.; Chierakul, W.; Chaowagul, W.; Anunnatsiri, S.; Phimda, K.; Mootsikapun, P.; Chaisuksant, S.; Pilaikul, J.; Thinkhamrop, B.; Phiphitaporn, S.; Susaengrat, W.; Toondee, C.; Wongrattanacheewin, S.; Wuthiekanun, V.; Chantratita, N.; Thaipadungpanit, J.; Day, N. P.; Limmathurotsakul, D.; Peacock, S. J., Trimethoprim-sulfamethoxazole versus trimethoprim-sulfamethoxazole plus doxycycline as oral eradicative treatment for melioidosis (MERTH): a multicentre, double-blind, non-inferiority, randomised controlled trial. Lancet 2014, 383 (9919), 807-14. [10.] U.S. National Library of Medicine. Medline Plus: Trusted Health Information for You. https://www.nlm.nih.gov/medlineplus/druginfo/meds/a684026.html. (accessed Feb 07, 2016). [11.] Cheng, A. C.; McBryde, E. S.; Wuthiekanun, V.; Chierakul, W.; Amornchai, P.; Day, N. P.; White, N. J.; Peacock, S. J., Dosing regimens of cotrimoxazole (trimethoprim-sulfamethoxazole) for melioidosis. Antimicrob Agents Chemother 2009, 53 (10), 4193-9. [12.] https://scifinder.cas.org/scifinder/view/scifinder/scifinderExplore.jsf. (accessed Feb 07, 2016). <span style="font-family: Arial,Helvetica,sans-serif;">[13.]https://pubchem.ncbi.nlm.nih.gov/compound/358641#section=Top.(accessed Feb 07, 2016). <span style="font-family: Arial,Helvetica,sans-serif;">[14.] US National Institute of Health. Clinical Trials. https://www.clinicaltrials.gov/ct2/show /NCT01420341?term=co-trimoxazole&rank=4. (accessed Feb 07, 2016).
 * <span style="font-family: Arial,Helvetica,sans-serif;">References: **

<span style="font-family: Arial,Helvetica,sans-serif;">External links:
http://www.mayoclinic.org/drugs-supplements/sulfamethoxazole-trimethoprim-oral-route/description/drg-20071899 http://www.medicinenet.com/melioidosis/article.htm

=<span style="font-family: Arial,Helvetica,sans-serif;">Target Information: = Dihydrofolate Reductase (DHFR) found in all dividing cells as a 186 amino acid protein with many secondary structural elements. It is a very important enzyme in producing co factors for cell division [5].



<span style="font-family: Arial,Helvetica,sans-serif;">Size: molecular weight of the protein
<span style="font-family: Arial,Helvetica,sans-serif;">20kDa [4]

<span style="font-family: Arial,Helvetica,sans-serif;">Location:
<span style="font-family: Arial,Helvetica,sans-serif;">Co-trimoxazole (TMP/SMX) inhibits the target by lowering the catabolic rate of the enzyme by turning off the protein. The first part of the drug, Sulfamethoxazole, first competes with para-aminobenzoic acid (PABA) to halt the production of dihydroholic acid. Then Trimethoprim, the second part of the drug, inhibits the production of the tetrahydrofolic acid binding to the active site of the enzyme dihydrofolate reductase. It does so by making a lack of dihydroholic in the environment to bind to the enzyme dihydrofolate reductase. By blocking the production of dihydrofolic acid this prevents the bacterium to reproduce [6].

<span style="font-family: Arial,Helvetica,sans-serif;">Function in a normal cell:
<span style="font-family: Arial,Helvetica,sans-serif;">The protein dihydrofolate reductase is normally found in the liver cell where it reduces dihydrofolic acid using NADPH and oxidizes tetrahydrofolic acid. The enzyme is expressed when there is a dihydrofolic acid present in the environment [5]. In general, it regulates the level of tetrahdrofolic acid which is essential for cell proliferation and cell growth. Inhibiting this protein would halt the replication of the bacterium causing the infection [6,7].



<span style="font-family: Arial,Helvetica,sans-serif;">Since the bacterium become resistant to the drug over a certain amount of time, taking Co-trimoxazole along with doxycycline would produce better results. However, experts such as Chetchotisakd suggest that Co-trimoxazole dosage is not inferior to co-trimoxazole with doxycycline as an oral treatment for Melioidosis [9]. In fact, it is specified that the combination of both Sulfamethoxazole and Trimethoprim can only resist target. Thus, the effectiveness of treating this system differs between individual.

=<span style="font-family: Arial,Helvetica,sans-serif;">Drug Information: = <span style="font-family: Arial,Helvetica,sans-serif;">Co-trimoxazole is that it has its own class of medication called sulfonamides. Sulfonamides do not kill viruses but halt its growth, making it a bacteriostatic [10 <span style="font-family: Georgia,serif;">]. Doses of the TMP/SMX vary between countries. In Australia the dose is 320/1600 mg, two double strengthen tablets while in Thailand the dosage is 160/800 mg.

<span style="font-family: Arial,Helvetica,sans-serif;">**Formula:**
<span style="font-family: Georgia,serif;">C14 H18 N4 O3. C10 H11 N3 O3 S (C24H29N7O6S) <span style="font-family: Arial,Helvetica,sans-serif;"> [12]

<span style="font-family: Arial,Helvetica,sans-serif;">Molecular weight:
<span style="font-family: Arial,Helvetica,sans-serif; line-height: 1.5;">543.59536 grams per mole [12]

<span style="font-family: Arial,Helvetica,sans-serif;">CAS Number:
<span style="font-family: Arial,Helvetica,sans-serif;">8064-90-2 [12]

<span style="font-family: Arial,Helvetica,sans-serif;">Delivery method:
<span style="font-family: Arial,Helvetica,sans-serif; line-height: 1.5;">Orally through the mouth of a tablet and/or a liquid suspension [10]

<span style="font-family: Arial,Helvetica,sans-serif;">Side effects:
<span style="font-family: Arial,Helvetica,sans-serif; line-height: 1.5;">Nausea, vomiting, loss of appetite [12]

<span style="font-family: Arial,Helvetica,sans-serif;">Other names:
<span style="font-family: Arial,Helvetica,sans-serif; line-height: 1.5;">4-amino-N-(5-methyl-1,2-oxazol-3-yl)benzenesulfonamide;5-[(3,4,5-trimethoxyphenyl) methyl]pyrimidine-2,4-diamine, the IUPAC name, Trimosulfa, trimethoprimsulfa, trimethoprim/ sulfamethoxazole, and the TMP/SMX [12]

<span style="font-family: Arial,Helvetica,sans-serif;">Maker or company:
<span style="font-family: Arial,Helvetica,sans-serif; line-height: 1.5;">Septra® and Bactrim®[12]

<span style="font-family: Arial,Helvetica,sans-serif;">Is it patented?
<span style="font-family: Arial,Helvetica,sans-serif; line-height: 1.5;">Suppliers such as SB_SCI_CORP, ChemTik, Alfa Chemistry, and ABI Chem have requested patented but has been no pending patents [13].

<span style="font-family: Arial,Helvetica,sans-serif;">Clinical Trials Info:
<span style="font-family: Arial,Helvetica,sans-serif;">There are 181 clinical trials on this drug to be administered to patients with Melioidosis. Currently, the study is recruiting participants between 12 to 20 weeks about the efficacy of administering this drug compared with other competing drugs [14].

<span style="font-family: Arial,Helvetica,sans-serif;">Origin:
<span style="font-family: Arial,Helvetica,sans-serif;">Melioidosis originates from a saprophytic environmental bacterium Burkholderia pseudomallei, in a soil and surface water [4]. It is not transmittable by humans but from the environment.

<span style="font-family: Arial,Helvetica,sans-serif;">Alternatives to this drug:
<span style="font-family: Arial,Helvetica,sans-serif; line-height: 1.5;">There are multiple alternatives to this drug that are administered during the eradication phase which are: chloramphenicol, only doxycycline, and Co-trimoxazole with doxycycline [4].

<span style="font-family: Arial,Helvetica,sans-serif;">Miscellaneous:
<span style="font-family: Arial,Helvetica,sans-serif; line-height: 1.5;">Used most often to treat 'travelers' diarrhea because it treats bacterial infection [10].

<span style="font-family: Arial,Helvetica,sans-serif; line-height: 1.5;">Other uses: can this drug be used to treat other diseases/conditions?
<span style="font-family: Arial,Helvetica,sans-serif; line-height: 1.5;">This drug can also be used to treat other similar and common bacterial infections such as pneumonia, bronchitis, and infections such as those from the urinary tract, ears, and the intestine [10].