Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Mar 3;18(3):e0282454.
doi: 10.1371/journal.pone.0282454. eCollection 2023.

In-vivo studies on Transitmycin, a potent Mycobacterium tuberculosis inhibitor

Rajesh Mondal  1 , Azger Dusthackeer V N  2 , Palaniyandi Kannan  2 , Amit Kumar Singh  3 , Kannan Thiruvengadam  2 , Radhakrishnan Manikkam  4 , Shainaba A S  2 , Mahizhaveni Balasubramanian  2 , Padmasini Elango  2 , Sam Ebenezer Rajadas  2 , Dinesh Bharadwaj  5 , Gandarvakottai Senthilkumar Arumugam  6 , Suresh Ganesan  6 , Hemanth Kumar A K  2 , Manjula Singh  7 , Shripad Patil  3 , Jaleel U C A  8 , Mukesh Doble  9 , Balagurunathan R  10 , Srikanth Prasad Tripathy  11 , Vanaja Kumar  11
Affiliations

In-vivo studies on Transitmycin, a potent Mycobacterium tuberculosis inhibitor

Rajesh Mondal et al. PLoS One. .

Abstract

This study involves the in-vitro and in-vivo anti-TB potency and in-vivo safety of Transitmycin (TR) (PubChem CID:90659753)- identified to be a novel secondary metabolite derived from Streptomyces sp (R2). TR was tested in-vitro against drug resistant TB clinical isolates (n = 49). 94% of DR-TB strains (n = 49) were inhibited by TR at 10μg ml-1. In-vivo safety and efficacy studies showed that 0.005mg kg-1 of TR is toxic to mice, rats and guinea pigs, while 0.001mg kg-1 is safe, infection load did not reduce. TR is a potent DNA intercalator and also targets RecA and methionine aminopeptidases of Mycobacterium. Analogue 47 of TR was designed using in-silico based molecule detoxification approaches and SAR analysis. The multiple targeting nature of the TR brightens the chances of the analogues of TR to be a potent TB therapeutic molecule even though the parental compound is toxic. Analog 47 of TR is proposed to have non-DNA intercalating property and lesser in-vivo toxicity with high functional potency. This study attempts to develop a novel anti-TB molecule from microbial sources. Though the parental compound is toxic, its analogs are designed to be safe through in-silico approaches. However, further laboratory validations on this claim need to be carried out before labelling it as a promising anti-TB molecule.

PubMed Disclaimer

Conflict of interest statement

Authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Structural comparison between TR and actinomycin.
Fig 2
Fig 2. The extent that the MICs (n = 50) differ from the observed critical concentration (CC) of TR in comparison to INH, RIF, BDQ, KAN, MXF, and DEL.
Fig 3
Fig 3. MIC and MBCs of TR in 39 drug-resistant isolates of M. tuberculosis.
Fig 4
Fig 4. Plot of Kaplan-Meier survival analysis (survival curve) for four groups of guinea pigs after Transitmycin administration is depicted.
In this study, the outcome event of mortality after third dose of drug was observed at concentrations with median survival time 0.01mg/kg 13[12-15days], 0.02mg/kg 7[7-8days] and 0.04mg/kg 6[6-7days] respectively. Further, all the animals survived at 0.001mg/kg (n = 6/6) concentration for 15 days.
Fig 5
Fig 5. In-vitro anti-TB efficacy testing on TR analogues by LRP assay.
See this image and copyright information in PMC

References

    1. Murray JF, Schraufnagel DE, Hopewell PC. Treatment of Tuberculosis. A Historical Perspective. Annals of the American Thoracic Society. 2015;12(12):1749–1759. doi: 10.1513/AnnalsATS.201509-632PS - DOI - PubMed
    1. Iseman MD. Tuberculosis therapy: past, present and future. European Respiratory Journal. 2002;20(36 suppl):87S LP–94s. http://erj.ersjournals.com/content/20/36_suppl/87S.abstract. - PubMed
    1. Sensi P. History of the development of rifampin. Reviews of infectious diseases. 1983;5 Suppl 3:S402–6. doi: 10.1093/clinids/5.supplement_3.s402 - DOI - PubMed
    1. Pablos-Méndez A, Raviglione MC, Laszlo A, Binkin N, Rieder HL, Bustreo F, et al.. Global surveillance for antituberculosis-drug resistance, 1994–1997. World Health Organization-International Union against Tuberculosis and Lung Disease Working Group on Anti-Tuberculosis Drug Resistance Surveillance. The New England journal of medicine. 1998;338(23):1641–1649. doi: 10.1056/NEJM199806043382301 - DOI - PubMed
    1. Dye C, Espinal MA. Will tuberculosis become resistant to all antibiotics? Proceedings. Biological sciences. 2001;268(1462):45–52. https://pubmed.ncbi.nlm.nih.gov/12123297. doi: 10.1098/rspb.2000.1328 - DOI - PMC - PubMed

Publication types

Substances