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

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.

Protective effect of antigen excess immune complex in guinea pigs infected with Mycobacterium tuberculosis.

Background & objectives: : Immune complexes (ICs) play a crucial role which can either be beneficial or pathological to the host. Involvement of circulating immune complexes (CICs) has been shown in tuberculosis (TB) cases (adults and neonates form), but its immunomodulatory effect has not been studied in vivo. Hence, this study was carried out to understand and explore the prognostic therapeutic potential of CICs on the host immune system in guinea pigs animal TB model. Methods: In this study, the guinea pigs (group I) were immunized with in vitro synthesized antigen excess IC (AgX-IC), group II with antibody excess IC (AbX-IC) and group III with phosphate-buffered saline. All these animals were sensitized with Mycobacterium tuberculosis H37Rv before immunization and subsequently infected with M. tuberculosis H37Rv strain post-immunization with IC. Results: Mortality was observed in animals belonging of groups II and III, while all animals in group I survived. A steady increase in the body weight of animals immunized with AgX-IC was observed when compared to the other groups. The infection load in the spleen and lungs was less in animals from group I when compared to the other groups. The CICs were found to be in higher concentration in serum of IC-immunized guinea pigs when compared to ICs non-immunized animals. Interpretation & conclusions: Based on our findings, it can be speculated that the ICs may have a protective immunomodulatory role pertaining to disease progression and development of pathology. As a new perspective, with further insight into the underlying mechanism of action and correlation with clinical data, ICs may also be used as a potential tool for assessing the immune status of the infected individuals, especially the close contacts of TB patients.