Preclinical evaluation of novel antibiotic transitmycin isolated from
novel marine Streptomyces species R2
The global burden of the Tuberculosis (TB) disease is huge leading to nearly 1.7
million cases per year and 4,700 deaths per day with one person dying of TB worldwide
in every 20 seconds. No novel drug has been introduced into the regimen for TB for the
last four decades. Actinomycetes are potential source of novel antibiotics against
Mycobacterium tuberculosis. The compound transitmycin (Tr) isolated from a novel
marine Streptomyces sp. was found to be acting on both tubercle bacilli and HIV. It
needs to be fully exploited against latent TB bacilli, HIV and cancer too. The ideal
growth conditions of the producing strain need to be standardized and optimized. The in
silico studies will enable us to refine the compound and its pharmaceutical ingredients.
The bioinformatics analysis and QSAR studies will pave way for deciphering its drug
targets leading to computer aided drug designing. Thus the drug discovery and treatment
scenario of TB will be altered in a big way by embarking on this journey of transitmycin.
Preliminary work done by the Investigators:
(i) Anti TB activity
Tr showed good anti tuberculous activity against drug sensitive, drug resistant
(MDR & XDR) strains and latent bacilli of M. tuberculosis by LRP assay.
(ii) Anti-HIV activity
Anti-viral activity of tr was assessed during infection of PBMC with HIV-1(IIIB).
293T cells were transfected with 20g of HIV-1 (IIIB) plasmid DNA using the
mammalian cell transfection kit (Millipore). The culture supernatant was collected 48
hours post-transfection, clarified by centrifugation and virus titer was determined.
A reduction in p24 levels was observed in the presence of compound,
clearly indicating that the compound had an inhibitory effect against all clades of HIV
including A,B,C,D,E, recombinant clade AC as well as the clades resistant to AZT and
Neverapin .
Methodology:
Antioxidant activity of transitmycin;
DPPH radical scavenging activity of transitmycin ;
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Superoxide anion scavenging activity of transitmycin;
Hydroxyl radical scavenging activity of transitmycin;
Bioinformatics studies on transitmycin:
The main goal of this study is to identify potential protein targets along with the offtargets that will be capable of binding to transitmycin.
Phamacophore based identification for structurally similar small molecules from
small molecule databases.
Pharmacophore is the spatial arrangement of features essential for a small molecule to
interact with a specific target receptor and very important for predicting molecular
interaction. Here we aim to identify structurally similar molecules from ZINC databases
based on defined pharmacophore properties.
Direct Affinity Responsive Target Stability (DARTS) - for identifying and
confirming target proteins.
DARTS is a method for target identification that relies on drug-induced protease
resistance. This method aims to discover the direct binding targets (and off targets) of
small molecules on a proteome scale without requiring chemical modification of the
compound. This method can be used for identifying targets of Mycobacterium
tuberculosis as well for confirming the binding of Transitmycin to the predicted protein
targets based on the above methodologies.
Outcomes of the proposed proposal
 The conditions for better production of transitmycin will be optimized.
 The bulk preparation of transitmycin will be possible using the optimized fermentation
medium components and culture conditions.
 The transitmycin derivatives with improved antiTB activity compared to transitmycin
are to be synthesized.
 The finding from this study will lead to drug formulation studies and its preclinical
toxicological testing.
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TOTAL BUDGET FOR THE PROJECT AFTER COLLATION OF THE
COLLABORATING INSTITUTES
PI (TRC)
Staff
Contingency
Recurring
Non recurring [equipment]
Travel
TOTAL
Overhead Charges [5%]
Total
12,44,196
1,20,000
65,00,000
15,00,000
80,000
84,44,196
4,22,210
88,66,406
Grant Total
CO-PI
(TRC)
10,50,000
6,00,000
50,00,000
25,00,000
6,00,000
97,50,000
4,87,500
1,02,37,500
CO-PI (IIT,
CHENNAI)
11,22,000
3,00,000
11,85,000
75,00,000
3,00,000
1,04,07,000
5,20,350
1,09,27,350
CO-PI
(PERIYAR
UNIVERSITY)
9,36,000
1,50,000
9,40,000
18,00,000
1,50,000
39,76,000
1,98,800
41,74,800
3,42,06,056
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