NAMAN SHAH POLY ID-0396904


Discovery and Development of “Jainin” for the treatment of Pulmonary
Tuberculosis caused by M...
Contents

Sr. No.      Title                                             Page
 1]   Brief account on Pulmonary Tuberculosi...
[1] Introduction to TUBERCULOSIS
Tuberculosis is primarily caused by aerobic bacterium-Mycobacterium tuberculosis

SYMPTOM...
[2] Is there a medical need to develop a new drug?

    Table 1: Comparison of existing drugs in the market
DRUG [15,16,18...
[3] TARGET for the new drug:
My target is Isocitrate lyase which is the enzyme involved in the Glyoxylate cycle in
M.tuber...
[4] Assay for evaluating Inhibitor of Isocitrate Lyase for developing anti-
tuberculosis drug:-
Reagents and Materials req...
[5] Lead Optimization and Selection of animal model:-
The NCE structures are as follows:
                                 ...
many reagents to study the pathological parameters which are not available in other models. Other
close contender is the g...
Table 3: Structural formula of NCEs

                  R1                         R2                    R3

 Lead         ...
Conclusion: From the pharmacokinetic values, NCE 1 is the best suited NCE to choose for animal
studies as it can be seen t...
[7] Biomarkers used for clinical trials of pulmonary tuberculosis:
CD11c [7]:

CD11c is involved in phagocytosis of M.tube...
[8]Phase 1 clinical trial for study of Isocitrate lyase inhibitor for treatment of
tuberculosis [15]
Purpose: This study i...
[9] Phase-2 clinical trial to determine the dosage and safety of Isocitrate lyase
inhibitor [15]:
Purpose: To evaluate saf...
Phase 3 clinical trials for Isocitrate lyase inhibitor (Jainin):

Efficacy and safety study of Isocitrate Lyase inhibitor ...
About 85% of the patients administered with JAININ showed relief in their tuberculosis symptoms. The
CD11c levels went dow...
Summary of Clinical Trials:

Table 7:
 Key points for Phase1            Key points for Phase 2           Key points for Ph...
NDA Application:

Sufficient data is gathered after successful completion of phase 3 trials for filing of NDA approved
app...
Appendix:
APPENDIX-1

There have been many cases of drug resistance in tuberculosis but still the standard treatment regim...
19 | P a g e
References:

[1] Bing Bai, Jiang-Ping Xie, Ju-Fang Yan, Hong-Hai Wang, Chang Hua Hu. 2006. A High
Throughput Screening App...
[18] www.healthscout.com

[19] www.pubmedcentral.nih.gov

[20] www.rxlist.com

[21] www.sciencemag.org

[22] www.wikipedia...
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New Drug For Tb

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New Drug For Tb

  1. 1. NAMAN SHAH POLY ID-0396904 Discovery and Development of “Jainin” for the treatment of Pulmonary Tuberculosis caused by Mycobacterium tuberculosis Abstract/Summary: Pulmonary tuberculosis is the cause behind the death of 1.7 million people every year. The standard treatment spans for 6 long months with stringent regimen. Patient compliance is difficult to achieve which many times result in incomplete course of the medicine. This results in drug resistance in the patients. As such Mycobacterium tuberculosis is a very hardy bacterium and drug resistance makes it more difficult in treating the disease successfully. Moreover, the side effects of existence drugs are unfathomable and give great mental and physical pain to the patient. “Jainin” is the drug developed to counter all these and make the treatment of pulmonary tuberculosis viable, successful and more generous on the patient. The treatment time reduces to about 4 months with little or no side effects and virtually 100% curability. 1|Page
  2. 2. Contents Sr. No. Title Page 1] Brief account on Pulmonary Tuberculosis 3 2] Medical need for a new drug for Pulmonary Tuberculosis 4 3] Target for new drug 5 4] Assay and structure of the lead 6 5] Lead Optimization 7 6] Pharmacological profiling of NCE 8 7] Biomarkers 11 8] Clinical Trials Phase 1 12 Phase 2 13 Phase 3 14 9] Appendix 18 10] References 20 2|Page
  3. 3. [1] Introduction to TUBERCULOSIS Tuberculosis is primarily caused by aerobic bacterium-Mycobacterium tuberculosis SYMPTOMS AND PROGRESSION [21, 22] Typical symptoms include: • Fever, chills, chest pain, weakness • Coughing up of blood • Night sweats, appetite loss, weight loss • Tuberculous pleuritis[1] KIND OF PEOPLE AFFECTED & PREVALANCE OF TUBERCULOSIS [9] • Annually 8 million people get infected with tuberculosis out of which 2.2 million people develop tuberculosis. • Tuberculosis is prevalent among all age groups but the age group of 25-44 has shown the largest increase. • Mostly people in the developing countries are at a greater risk. TREATMENT [5] • In the short treatment, isoniazid, rifampicin, pyrazinamide and ethambutol is given for two monthsand then isoniazid and rifampicin are given for 4 months. • The course runs for 6 months. • Isoniazid is given for 9 months in latent tuberculosis.[21] DIAGNOSIS [5] • Chest X-ray gives a relevant idea of presence of tuberculosis. • Microbial examinations of the sputum of the patient can also diagnose the disease. The examinations include fluorescence microscopy. • Bronchoscopy, biopsy and PCR can also be used to detect M.tuberculosis.[21] • Tuberculin skin test like Mantoux test and Heaf test are used to detect the presence of tuberculosis. 3|Page
  4. 4. [2] Is there a medical need to develop a new drug? Table 1: Comparison of existing drugs in the market DRUG [15,16,18] MANUFACTURER[17] MODE OF FREQUENCY[8] SIDE EFFECTS[18] ADMINISTRATION[19] ISONIAZID 1)Nydrazid Bristol-Myers Oral 5 mg/kg up to 300mg 1)Severe/fatal Squibb in a single dose; or 15 hepatitis mg/kg up to 900 2)Peripheral mg/day 2 or 3 times a neuropathy week 3)hypersensitivity reactions 4)Nausea, vomiting In combination 1)Ataxia, fatigue with Rifampin 2)Diarrhea, nausea 2)Rifamate Aventis Oral 3)Hepatitis Pharmaceuticals 2 capsules once daily 4)Acute renal failure In combination with Rifampin 1)Jaundice & 2)Thrombocytopenia pyrazinamide 3)Cerebral 1)Rifadin Aventis Oral or Injection IV hemorrhage Pharmaceuticals 10 mg/kg once a day 4)Visual disturbances ETHAMBUTOL 1)Myambutol- Elan Oral 1)Decrease in visual along with pharmaceuticals 15mg/kg once a day acuity isoniazid 2)Dermatitis 3)Hypersensitivity 4)Acute gout MEDICAL NEED:- As it is evident from the side effects caused by the drugs there is an imminent need to develop a new drug for treating tuberculosis. The standard treatment involves 6 months which is too long. Also, cases of drug resistance are observed more often than not which compels us to think differently and devise new drugs which are more effective and consume less time. A finding by WHO indicates that tuberculosis falls under the neglected diseases as pharmaceutical companies are not that keen to devise new drugs. Lastly, every year 1.7 million people die due to tuberculosis. So, there is absolutely very dire need to develop new drug for treating tuberculosis. 4|Page
  5. 5. [3] TARGET for the new drug: My target is Isocitrate lyase which is the enzyme involved in the Glyoxylate cycle in M.tuberculosis Role of Isocitrate lyase: • It has been found out through various transcriptional studies that M.tuberculosis depends more on the fatty acids for survival rather than the carbohydrates in the host body. • The bacterium has several enzymes which are related to fatty acid metabolism-34 acyl- CoA synthases, 34 acyl-CoA dehydrogenases, 21 enoyl CoA hydratases, six 3- hydroxyacyl-CoA dehydrogenases and six acetyl-CoA C-acetyltransferases. • It contains more than 250 lipid metabolizing enzymes which show the importance of fatty acid metabolism in the bacterium. • Isocitrate lyase is also required for the fatty acid catabolism and virulence in the organism. • Individual deletion of the genes coding for the 2 isoforms of the enzyme does not have any effect on the catabolism but simultaneous deletion of the genes results in total impairment of intracellular replication. Isocitrate lyase as a target: • Glyoxylate cycle is very important in bacteria for their metabolism. • A knockout of enzyme Isocitrate lyase can completely impair the glyoxylate cycle in the organism. • Due to this, there occurs a problem in the glyoxylate pathway which ultimately results in the disruption of the metabolism of fatty acids. • As a result, the organism cannot maintain its regular physiological processes and ultimately dies. • A drug can be devised which specifically targets this lyase. • As a result the enzyme is denatured and the organism is killed. Advantages of this drug as compared to the marketed drugs: • Currently available drugs in the market are highly efficient but lead to fatal side effects. • Also, there is a high rise in the cases of resistance against these drugs which is posing a big problem in successfully treating the disease. • Also, current drugs find it difficult to treat the dormant bacteria in the granulomas. • The new drug implies a new target which can successfully counter the resistance aspect. • Moreover, it might be able to cure the disease in a short period as compared to current drug time span as it is also effective on the dormant bacteria which are enclosed in the granulomas. In fact it is more effective on the dormant bacteria as they live in hypoxic conditions and hence need fatty acid metabolic pathways more than the bacteria in the blood stream. • Also, Isocitrate lyase is specific for the glyoxylate cycle which is not present in humans. Due to this there is no effect on human beings. The drug will only act on ICL and nothing else, so the possibility of side effects is greatly reduced. 5|Page
  6. 6. [4] Assay for evaluating Inhibitor of Isocitrate Lyase for developing anti- tuberculosis drug:- Reagents and Materials required: M.tuberculosis culture, Pfu DNA Polymerase, DNA Ligase, dNTP, Isocitrate Lyase, Inhibitory compound derived from Itaconic anhydride, 96-well plate, Biomek FX [1] Assay for checking the inhibitory effect: The assay is divided into 2 parts-1) Checking the enzymatic activity, 2) Checking the inhibitory effect of the compound under study. [1] 1) Checking the enzyme activity [1]: The formation of glyoxylate-phenylhydrazone was checked in presence of phenylhydrazine and • isocitrate lyase when the enzyme was incubated at 370C. The reaction mixture of buffer and isocitrate lyase and phenyl hydrazine was kept for 10 • minutes for incubation and then the absorbance was measured at 324 nm after the addition of isocitrate. Buffer was composed of potassium phosphate, MgCl2, phenylhydrazine, and cysteine. • 2) HTS checking of the inhibitory effect of the compound under study [1]: 10 micro liter of the inhibitory substance was added into a 96-well plate. Into that, 178 micro • liters of reaction buffer, 10 micro liters compound solution, 2 micro liters recombinant protein ICL solution and 10 micro liter of isocitrate solution was added. It was allowed to incubate for some time. Then absorbance was measured at 324 nm. The activity of the enzyme was determined by change in the absorbance values. • Inhibitory substance+ Reaction buffer+ ICL +Isocitrate+ Phenyl hydrazine Glyoxylate- Phenylhydrazone Change in Absorbance Lead Structure [1, 13]: OH C NH2 H2C C O CH O HOOC Figure 1 6|Page
  7. 7. [5] Lead Optimization and Selection of animal model:- The NCE structures are as follows: HO OH CH2 HO Cl HS NH2 O OH O OH Cl N NH2 Br CH2 OH Cl CH2 Cl HO Cl NH2 OH O O OH OH Figure 2 (a, b, c, d) Animal model [2, 3, 4]:- There are basically 4 models available for the study of Tuberculosis. They are- Table 2: Animal model selection MICE RABBIT GUINEA PIG RHESUS MONKEY Mode of infection is Shows a spectrum of Highly susceptible Susceptibility and subcutaneous or disease-represent towards the disease. progression of disease intravenous specific stages of is like humans human disease Low cost Low-medium cost High cost High cost Aggregation of the The inbred are more They granulomas The granulomas are lymphocytes is towards susceptible compared exhibit many similarities similar to humans the center in the to outbred. to human granulomas. granuloma Has innate resistance Has Innate resistance No resistance-Show Many reagents to study towards tuberculosis towards tuberculosis lung tissue necrosis, pathological which is a negative lose weight, die-like parameters. point for studies. humans Easily available Large numbers required High rearing cost can be Can spread infection to countered by high other monkeys. susceptibility Animal of choice: - Rhesus monkeys with SCID are best suited for the studies as they resemble the humans very closely as far as the disease progression and symptoms are concerned. Also, there are 7|Page
  8. 8. many reagents to study the pathological parameters which are not available in other models. Other close contender is the guinea pig which shows exceptional susceptibility towards the disease. But the monkey is chosen ahead due to its similarity and efficacy of the drug in it. Mice and rabbits show innate resistance which is not useful. Monkeys might spread infection but it can be dealt with. The cost is little higher but the results are worth the cost. So, Rhesus monkey with SCID is the animal of choice. [6] Pharmacological profiling of NCE [10]: LEAD Cl HO OH NH2 CH2 CH2 HO HO Cl Cl HS HS NH2 NH2 O O OH OH O O OH OH NCE1 NCE 2 Cl N NH2 Br CH2 OH Cl CH2 Cl HO Cl NH2 OH O O OH OH NCE 3 NCE 4 Figure 3 (a, b, c, d, e) 8|Page
  9. 9. Table 3: Structural formula of NCEs R1 R2 R3 Lead -H -H -H NCE(1) -O-CH2-SH -NH2 NH2 Cl OH NCE(2) -O-CH2-SH -NH2 OH Br NH2 NCE(3) -NH2 Cl NCE (4) -H N H Cl Table 4: Pharmacological profiling % GSH depletion[4] IC50[16] Absorption rate by P450 Inhibition (%)[4] Caco-2 screening assay (cm sec-1)[4] 12 x 10-6 NCE 1 8 4 1.2 uM 9 x 10-6 NCE 2 40 27 7 uM 8 x 10-6 NCE 3 72 53 3.2 uM 6 x 10-6 NCE 4 24 37 4.1 uM 9|Page
  10. 10. Conclusion: From the pharmacokinetic values, NCE 1 is the best suited NCE to choose for animal studies as it can be seen that, in all the 4 screens that are selected as testing parameters, the values of NCE 1 are good. The absorption rate obtained by Caco 2 assays suggest that the absorption of NCE 1 is better. The %P450 inhibition of NCE 1 is 8 which shows that it is better. The % GSH inhibition is also low which suggests that NCE 1 is less toxic. The IC50 value is 1.2 uM which is good because at that low concentration 50% of enzyme gets inhibited. In case of other NCEs the IC50 values are high which is not good. Also, the molecular weight is 459.34, LogP is 2.57 and N+O is 7 which follows the Lipinski rule. The presence of –Cl, NH2, OH, COOH, SH groups makes it hydrophilic while the presence of 2 benzene ring structures makes it hydrophobic. So stronger binding can be achieved. Hence, it can be seen that NCE 1 is good enough and should proceed ahead with animal studies. Route of Administration of drug: Based on the studies performed on animal model, the route of administration of the drug will be oral for all further studies. Patent of NCE: The most effective NCE determined through in vitro pharmacological profiling and animal studies is patented under the patenting regulatory authority. Summary of Pre-IND activities: Duration: 3 years Research to generate Lead Efficacy and mechanism of action studies Animal model selection-SCID Rhesus monkey(dose exposure, metabolism) & route of administration-oral Kinetic studies to check drug-drug metabolism, effect on enzymatic activity Safety pharmacology study (Pharmacological profiling-ADMET studies) Toxicology under GLP Single dose toxicity study Safety studies including range finding Genotoxicity study Drug impurity determination IND filing 10 | P a g e
  11. 11. [7] Biomarkers used for clinical trials of pulmonary tuberculosis: CD11c [7]: CD11c is involved in phagocytosis of M.tuberculosis by macrophages. Tuberculosis patients have an elevated level of CD11c on blood monocytes as compared to normal and healthy people. When anti-tuberculosis treatment is done then the levels of CD11c come down. So, CD11c can be used as a biomarker for evaluating the efficacy of the drug. sIL-2Rα, sTNF-R1, sTNF-R2 [8] : sIL-2Rα, sTNF-R1 and sTNF-R2 can be used as biomarkers for testing the efficacy of the tuberculosis treatment. Before treatment the levels of all the 3 are relatively high in the patients. After subsequent treatment, the levels of these biomarkers go down even in slow treatment responders. So, the above mentioned biomarkers can be used as efficacy biomarkers in monitoring the efficacy of the drug for treatment of tuberculosis. 11 | P a g e
  12. 12. [8]Phase 1 clinical trial for study of Isocitrate lyase inhibitor for treatment of tuberculosis [15] Purpose: This study is targeted to find out the safety and tolerability of an increasing dose of Isocitrate lyase inhibitor by administering it into adult volunteers. Condition: Tuberculosis Intervention: Isocitrate lyase inhibitor Phase: Phase-1 Study type: Interventional Study design: Safety and efficacy study, Dose comparison, treatment ELIGIBILITY Age: 18 to 60 years Gender: Both Healthy Volunteers: No Number of volunteers: 90 Doses taken of NCE: From the results obtained from the trials on animal model the range of dose is selected. The minimum effective dose was 10mg/kg and maximum tolerated dose was 200 mg/kg. 1/10th of this MTD was taken in the clinical trials which turned out to be 20 mg/kg. Table 5: Results for Phase-1 trials Dose (mg/kg) No of Subjects No of Adverse Events Average CD11c level (%) * 20 30 1-Nausea 60 40 30 2-Nausea, Fatigue, 40 80 30 3-Nuasea, Vomiting, Fatigue 6 *100% stands for total amount of CD11c receptors on the Phagocytes before the treatment of the patient began. Adverse event: Nausea is seen as a common side effect in majority of patients. It might be resulting due to the creation of heaviness in the stomach as the drug may draw water from the cells. This withdrawal of water might be due to the changes in osmotic pressure across the cells of stomach. Also, vomiting and fatigue are observed. Conclusion: From the phase-1 trials the hMTD is 80mg/kg. The drug is well tolerated as it is not giving major side effects. 12 | P a g e
  13. 13. [9] Phase-2 clinical trial to determine the dosage and safety of Isocitrate lyase inhibitor [15]: Purpose: To evaluate safety of the drug and determine its effective dosage. Study type: Interventional Study design: Safety and efficacy study, placebo, treatment Eligibility: Age: 18 to 60 years Gender: Both Healthy volunteers: No Number of volunteers: 180 Criteria [15]: Inclusion criteria: • Sputum positive patients and patients previously treated for more than 1 month as per RNTCP/WHO guidelines. • Radiographic evidence of the disease. • High WBC count. High WBC count symbolizes mycobacterial infection. • Microbiological confirmation of Mycobacterial infection. • Patients with treatment failure, disease relapse as it helps in establishing the superiority of the drug. Exclusion criteria: • Subjects below 18 years are not included as the drug might behave differently. • Pregnant, breast feeding women in order to prevent the drug from going inside the baby. • Patients with systematic cancer chemotherapy which may result in false side effects. • Patients who are also infected with HIV, Hepatitis B or C as these infections make treatment difficult. Table 6: Results for phase-2 trials Dose (mg/kg) no of subjects No of Adverse events Average CD11c level (%) * 15 60 1-Nausea 65 30 60 3-Nuasea,Bowel upset, fatigue 45 4-Nausea, Indigestion, Fatigue, 60 60 7 Vomiting *100% stands for total amount of CD11c receptors on the Phagocytes before the treatment of the patient began. Adverse events: Apart from the side effects observed in phase 1 trials which were also observed in phase 2, bowel upset was observed in subjects. In some of the subjects, indigestion was also observed. Conclusion: Phase 1 and 2 trials are giving sufficiently good results with fewer side effects to proceed ahead with the phase 3 trials. The side effects are very marginal. Dose should be 50mg/kg. 13 | P a g e
  14. 14. Phase 3 clinical trials for Isocitrate lyase inhibitor (Jainin): Efficacy and safety study of Isocitrate Lyase inhibitor in Pulmonary Tuberculosis patients Purpose of this study is to evaluate the efficacy, safety, side effects and decrease in daily dosage of drug for treating pulmonary tuberculosis. Study design: treatment, safety, efficacy, drug lowering Study type: interventional Placebo controlled trial [15]: Currently there are no drugs being developed which inhibit Isocitrate Lyase. So my study will tested against a placebo to get a clear idea of the effect of the drug. Drugs for tuberculosis are known to give various side effects. Also, tuberculosis is a stubborn disease with large amount of resistance. So a placebo controlled study would be ideal in order to study the side effects as well as efficacy. Primary endpoints [15]: Number of days required for the sputum culture to turn to negative. Treatment success rate at the end of 4 months. Adverse effects during the study Secondary endpoints [15]: Tuberculosis cure rate CD4 T Lymphocytes Dose: 50mg/kg Eligibility [15] Age- 18 to 60 years Sex- Both Healthy volunteers- No Inclusion criteria: • Sputum positive patients and patients previously treated for more than 1 month as per RNTCP/WHO guidelines. • Radiographic evidence of the disease. • High WBC count. High WBC count symbolizes mycobacterial infection. • Microbiological confirmation of Mycobacterial infection. • Patients with treatment failure, disease relapse as it helps in establishing the superiority of the drug. • Ability and willingness to give written consent as it is a high risk study. Exclusion criteria: • Subjects below 18 years are not included as the drug might behave differently. • Pregnant, breast feeding women in order to prevent the drug from going inside the baby. • Patients with systematic cancer chemotherapy which may result in false side effects. • Patients who are also infected with HIV, Hepatitis B or C as these infections make treatment difficult. • Severely malnourished patients as proper nutrition is very essential especially proteins. Results: A total of 1200 patients went through phase 3 clinical trials for the drug JAININ against placebo controlled trial. About 25% were given placebo. 14 | P a g e
  15. 15. About 85% of the patients administered with JAININ showed relief in their tuberculosis symptoms. The CD11c levels went down which showed successful treatment of tuberculosis. There were side effects in about 10% of population. Side Effects [17]: Anticipated side effects may not include any specific symptom as the drug targets isocitrate lyase which is a bacterial specific enzyme and not present in humans. So it is highly unlikely that the drug may cause any problems in humans. And this property is one of the high points of this drug. Nausea, weakness or fatigue might be observed. General energy drinks may be given to remove the weakness or fatigue. Drug Administration Regimen: Based on the clinical trials, the dosage for patients of 18 years and older is 50mg/kg tablet every day. For patients under 18 years-the dosage should be determined by physician depending upon case to case basis. 15 | P a g e
  16. 16. Summary of Clinical Trials: Table 7: Key points for Phase1 Key points for Phase 2 Key points for Phase 3 NDA Gateway to Phase Submission to Gateway to Phase 2 Gateway to Phase 3 1Chemistry,Manufacturing NDA & decision CMC- CMC & Controls: 2 years characterization of Manufacturing • • Formulation of • drug process validation drug Check impurities, Product release • • Manufacturing • manufacturing specification process on small controls, product validation scale release Stability check-at • specifications, Bioassay, Assay for • least for 2 years stability(at least 1 purity and potency year) Non clinical study: Stability Indicating • Non clinical Toxicology study assay Exposure of drug for 3 months-need 6 month Single and repeat Toxicology study • rodent & non rodent dose studies Genotoxicity study • Genotoxicity study • Single and repeat • Reproductive toxicity dose studies • Evaluation of potential for Reproductive & • delayed ventricular developmental repolarization toxicity studies. Starting dose is defined based on non clinical study Phase 2 trials: Phase 1 trialsStudy is done Study is randomized, placebo Phase 3 trials: on healthy controlled,double blind indivisuals.Phase 1 study is Randomized, placebo randomized, dose efficacy study in the subjects controlled, double blind escalation study to having asthma. determine Maximum efficacy study in subjects Tolerated Dose(MTD) having asthma to know ,safety in human and safe efficacy and safety profile dose range in on large scale. human.Human Pharmacokinetics and exploratory end points are also studied 16 | P a g e
  17. 17. NDA Application: Sufficient data is gathered after successful completion of phase 3 trials for filing of NDA approved application form. Life cycle management for JAININ: Patent for the chemical structure of the drug will be filed. Patent for the most effective NCE will be filed. The whole manufacturing process will be filed for patenting after the process is standardized in the studies. Patent will be filed for the dosage after standardizing it in phase 2 studies. Application for FDA approval will be filed after successful completion of phase 3 studies. After approval the drug is ready to be launched. 17 | P a g e
  18. 18. Appendix: APPENDIX-1 There have been many cases of drug resistance in tuberculosis but still the standard treatment regimen include the above mentioned drugs as the resistance prevalence is not that much and these drugs can successfully treat the disease. In some cases multiple drug resistance is observed which is also at a small scale so the standard treatment is continued. APPENDIX-2 The present drugs-Isoniazid, Rifampin, Pyrazinamide and Ethambutol are highly effective in treating Tuberculosis but there is a problem with the side effects that they cause-liver problems being the most severe. Moreover, patient compliance is a big issue as the current treatment spans over 6 stringent months. My target is a new one and currently under study. It is based on a hypothesis, the efficacy of which is currently under experimental study. There is a problem with redundancy as there are more than one synthase in the bacterium and inhibiting one synthase might not be that much useful but a drug can be developed which selectively inhibits all the synthases or the genes coding for the synthases. Apart from the TAG synthase, isocitrate dehydrogense inhibition, pantothenate biosynthesis inhibition, targeting the respiratory chain, ribonucleotide reductase and ATP synthase can be other possible targets. They are all under experimental study. APPENDIX-3 18 | P a g e
  19. 19. 19 | P a g e
  20. 20. References: [1] Bing Bai, Jiang-Ping Xie, Ju-Fang Yan, Hong-Hai Wang, Chang Hua Hu. 2006. A High Throughput Screening Approach to Identify Isocitrate Lyase Inhibitors from Traditional Chinese Medicine Sources. Drug Development Research 67:818-823. [2] Dharmadhikari A.J., Nardell E.A. (2008) “What Animal models teach humans about tuberculosis.” Ernesto J., Upton Anna, Cherian Joseph, McKinney J.D., 2006. Role of Methylcitrate cycle in Mycobacterium tuberculosis metabolism, intracellular growth and Virulence [3] Gupta U.D., Katoch V.M. (2009) Animal models of tuberculosis for Vaccine development. Indian J Med Res 129, pp 11-18 [4] Li. A.P. Screening for human ADME/Tox drug properties in drug discovery. DDT Vol.6, No. 7 (2001) [5] McMurray D.N. (2001) Disease model: pulmonary tuberculosis [6] Prescott L, Harley J, Klein D, ed. (1999), Prescott’s Microbiology, McGraw Hill, USA [7] Rosas-Taraco AG (Rosas-Taraco, Adrian G.), Salinas-Carmona MC (Salinas-Carmona, Mario C.), Revol A (Revol, Agnes), Rendon A (Rendon, Adrian), Caballero-Olin G (Caballero-Olin, Guillermo), Arce-Mendoza AY (Arce-Mendoza, Alma Y.) Expression of CD11c in Blood Monocytes as Biomarker for Favorable Response to Antituberculosis Treatment [8] S Brahmbhatt, G F Black, N M Carroll, N Beyers, F Salker, M Kidd, P T Lukey, K Duncan, P van Helden, and G Walzl. Immune markers measured before treatment predict outcome of intensive phase tuberculosis therapy (2006) [9] Treatment of Tuberculosis. American Thoracic society, CDC, and Infectious Diseases Society of America. [10] www.avert.org [11] www.bindingdb.org [12] www.biomedcentral.com [13] www.bio-medicine.org [14] www.chexmexper.com [15] www.clinicaltrials.gov [16] www.familydoctor.org [17] www.fda.gov 20 | P a g e
  21. 21. [18] www.healthscout.com [19] www.pubmedcentral.nih.gov [20] www.rxlist.com [21] www.sciencemag.org [22] www.wikipedia.org [23] www.wrongdiagnosis.com 21 | P a g e

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