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A New Therapy to Take Down Tuberculosis

A New Therapy to Take Down Tuberculosis

The long-term treatment of tuberculosis (TB) sometimes leads to non-adherence to treatment resulting in multi drug resistance (MDR) and extensively drug-resistant (XDR) tuberculosis.

Inadequate bioavailability of the drug is the main factor for therapeutic failure which leads to the development of drug-resistant cases. Therefore, there is an urgent need to design and develop novel anti-mycobacterial agents minimizing the period of treatment and reducing the propagation of resistance at the same time.

We recently report the development of original and non-cytotoxic polycationic phosphorus dendrimers essentially of generations 0 and 1, but also of generations 2 to 4, with pyrrolidinium, piperidinium and related cyclic protonated amino groups on the surface, as new anti-tubercular agents active per se, meaning intrinsic activity.

The strategy is based on the phenotypic screening of a newly designed phosphorus dendrimer library (generation 0 to 4) against three bacterial strains : attenuated M. tuberculosis H37Ra, virulent M. tuberculosis H37Rv, and M. bovis BCG. The most potent polycationic phosphorus dendrimers are active against the three strains with MICs between 3.12 and 25.0 µg/ml. Both are irregularly shaped nanoparticles with highly mobile branches presenting a radius of gyration of 7 Å, a diameter of maximal 25 Å, and a solvent-accessible surface area of dominantly positive potential energy with very localized negative patches arising from the central N3P3 core which steadily interacts with water molecules.

The most interesting dendrimer called 2G0.HCl shows relevant efficacity against single drug resistant (SDR) M. tuberculosis H37Rv, resistant to Rifampicin, Isoniazid, Ethambutol, or Streptomycin).
Importantly, 2G0.HCl displayed significative in vivo efficacy based on bacterial counts in lung of infected Balb/C mice at the dose of 50 mg/kg oral administration once a day for two weeks, and superior efficacy in comparison to Ethambutol and Rifampicin the most efficient drugs reported up to now. These series of polycationic phosphorus dendrimers represent first-in-class drugs to treat TB infection, could fulfill the clinical candidate pipe of this high burden of infectious disease, and play a part in the continuous demand for new drugs.

Publication :
Safe Polycationic Dendrimers as Potent Oral In Vivo Inhibitors of Mycobacterium tuberculosis : A New Therapy to Take Down Tuberculosis
Serge Mignani,* Vishwa Deepak Tripathi, Dheerj Soam, Rama Pati Tripathi,* Swetarka Das, Shriya Singh, Ramakrishna Gandikota, Regis Laurent, Andrii Karpus, Anne-Marie Caminade, Anke Steinmetz, Arunava Dasgupta,* Kishore Kumar Srivastava,* and Jean-Pierre Majoral*
Biomacromolecules, 2021, https://doi.org/10.1021/acs.biomac.1c00355
LCC corresponding author : Jean-Pierre Majoral