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Metformin as a potential combination therapy with existing front-line antibiotics for Tuberculosis.

Vashisht R, Brahmachari SK - J Transl Med (2015)

Bottom Line: The evolution of various multi-drug resistant strains through genetic mutations or drug tolerant strains through bacterial persistence renders existing antibiotics ineffective.Hence there is need for the development of either new antibiotics or rationalizing approved drugs that can be utilized in combination with existing antibiotics as a therapeutic strategy.A comprehensive systems level mapping of metabolic complexity in Mtb revels a putative role of NDH-I in the formation of bacterial persistence under the influence of front-line antibiotics.

View Article: PubMed Central - PubMed

Affiliation: Academy of Scientific and Innovative Research, New Delhi, India. vashishtrv@gmail.com.

ABSTRACT
Tuberculosis (TB), the disease caused by Mycobacterium tuberculosis (Mtb) remains a global health concern. The evolution of various multi-drug resistant strains through genetic mutations or drug tolerant strains through bacterial persistence renders existing antibiotics ineffective. Hence there is need for the development of either new antibiotics or rationalizing approved drugs that can be utilized in combination with existing antibiotics as a therapeutic strategy. A comprehensive systems level mapping of metabolic complexity in Mtb revels a putative role of NDH-I in the formation of bacterial persistence under the influence of front-line antibiotics. Possibilities of targeting bacterial NDH-I with existing FDA approved drug for type-II diabetes, Metformin, along with existing front-line antibiotics is discussed and proposed as a potential combination therapy for TB.

No MeSH data available.


Related in: MedlinePlus

Metformin, an FDA approved drug for type-II diabetes as a potential combination therapy for Tuberculosis with existing antibiotics. a) Antibiotic targeting mycolic acid biosynthesis; b) systems-level changes resulting into the reduction of flux carrying capacity of glycolysis and citric acid cycle c) resulting re-routing of metabolic fluxes through de novo NAD biosynthesis pathway and electron transport through NDH-I d) possibility of targeting NDH-I with metformin.
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Fig1: Metformin, an FDA approved drug for type-II diabetes as a potential combination therapy for Tuberculosis with existing antibiotics. a) Antibiotic targeting mycolic acid biosynthesis; b) systems-level changes resulting into the reduction of flux carrying capacity of glycolysis and citric acid cycle c) resulting re-routing of metabolic fluxes through de novo NAD biosynthesis pathway and electron transport through NDH-I d) possibility of targeting NDH-I with metformin.

Mentions: In our previous analysis, by utilizing a comprehensive in silico systems approach, we probed the metabolism in Mtb to identify various metabolic mechanisms that may potentiate the formation of persister phenotype in Mtb when challenged with current front-line antibiotics of TB therapy (Figure 1) [3]. Our analysis reveled directional re-routing of metabolic fluxes through NAD de novo biosynthesis pathway (encoded by nadA ~ E operon) and respiratory chain complex – I (NDH-I, encoded by nuoA ~ N operon) in Mtb as a possible alternate mechanism of ATP generation that may facilitate the formation of a persister phenotype and hence demonstrate antibiotic tolerance (Figure 1) [3].Figure 1


Metformin as a potential combination therapy with existing front-line antibiotics for Tuberculosis.

Vashisht R, Brahmachari SK - J Transl Med (2015)

Metformin, an FDA approved drug for type-II diabetes as a potential combination therapy for Tuberculosis with existing antibiotics. a) Antibiotic targeting mycolic acid biosynthesis; b) systems-level changes resulting into the reduction of flux carrying capacity of glycolysis and citric acid cycle c) resulting re-routing of metabolic fluxes through de novo NAD biosynthesis pathway and electron transport through NDH-I d) possibility of targeting NDH-I with metformin.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4359515&req=5

Fig1: Metformin, an FDA approved drug for type-II diabetes as a potential combination therapy for Tuberculosis with existing antibiotics. a) Antibiotic targeting mycolic acid biosynthesis; b) systems-level changes resulting into the reduction of flux carrying capacity of glycolysis and citric acid cycle c) resulting re-routing of metabolic fluxes through de novo NAD biosynthesis pathway and electron transport through NDH-I d) possibility of targeting NDH-I with metformin.
Mentions: In our previous analysis, by utilizing a comprehensive in silico systems approach, we probed the metabolism in Mtb to identify various metabolic mechanisms that may potentiate the formation of persister phenotype in Mtb when challenged with current front-line antibiotics of TB therapy (Figure 1) [3]. Our analysis reveled directional re-routing of metabolic fluxes through NAD de novo biosynthesis pathway (encoded by nadA ~ E operon) and respiratory chain complex – I (NDH-I, encoded by nuoA ~ N operon) in Mtb as a possible alternate mechanism of ATP generation that may facilitate the formation of a persister phenotype and hence demonstrate antibiotic tolerance (Figure 1) [3].Figure 1

Bottom Line: The evolution of various multi-drug resistant strains through genetic mutations or drug tolerant strains through bacterial persistence renders existing antibiotics ineffective.Hence there is need for the development of either new antibiotics or rationalizing approved drugs that can be utilized in combination with existing antibiotics as a therapeutic strategy.A comprehensive systems level mapping of metabolic complexity in Mtb revels a putative role of NDH-I in the formation of bacterial persistence under the influence of front-line antibiotics.

View Article: PubMed Central - PubMed

Affiliation: Academy of Scientific and Innovative Research, New Delhi, India. vashishtrv@gmail.com.

ABSTRACT
Tuberculosis (TB), the disease caused by Mycobacterium tuberculosis (Mtb) remains a global health concern. The evolution of various multi-drug resistant strains through genetic mutations or drug tolerant strains through bacterial persistence renders existing antibiotics ineffective. Hence there is need for the development of either new antibiotics or rationalizing approved drugs that can be utilized in combination with existing antibiotics as a therapeutic strategy. A comprehensive systems level mapping of metabolic complexity in Mtb revels a putative role of NDH-I in the formation of bacterial persistence under the influence of front-line antibiotics. Possibilities of targeting bacterial NDH-I with existing FDA approved drug for type-II diabetes, Metformin, along with existing front-line antibiotics is discussed and proposed as a potential combination therapy for TB.

No MeSH data available.


Related in: MedlinePlus