Safe Polycationic Dendrimers as Potent Oral In Vivo Inhibitors of Mycobacterium tuberculosis: A New Therapy to Take Down Tuberculosis

Abstract

The long-term treatment of tuberculosis (TB) sometimes leads to non-adherence to treatment resulting in multi drug resistant (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.Here, we 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 amino groups on the surface, as new anti-tubercular agents active per se, meaning with 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 1G0,HCl and 2G0,HCl are active against all 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 is 2G0,HCl showing relevant efficacity against single drug resistant (SDR) M. tuberculosis H37Rv, resistant to Rifampicin, Isoniaid, 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 3 for two weeks, and superior efficacy in comparison to Ethambutol and Rifampicin. This series of polycationic phosphorus dendrimers represents 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.

Main-chain flexibility and hydrophobicity of ionenes strongly impact their antimicrobial activity: an extended study on drug resistance strains and Mycobacterium

“…Such selectivity of polycations was also reported previously for the alkylated dimethyl-aminopropyl poly-aspartamides, 47 poly(dimethylaminoethyl) methacrylate, 46 and cationic phosphorus dendrimers. 42 Activity against Mtb , for the discussed herein polymers, remains at similar levels to the previously reported ionenes (MIC values 2–40 μg mL −1 ). 33,42,45,47,48 For example, an ionene with a structure similar to C0-T-p, studied by J. Tan et al , displayed a MIC value of 16 μg mL −1 against different Mtb strains.…”

“…42 Activity against Mtb , for the discussed herein polymers, remains at similar levels to the previously reported ionenes (MIC values 2–40 μg mL −1 ). 33,42,45,47,48 For example, an ionene with a structure similar to C0-T-p, studied by J. Tan et al , displayed a MIC value of 16 μg mL −1 against different Mtb strains. 33…”

“…52 Intriguingly, the high selectivity toward mycobacteria over Staphylococcus aureus and Escherichia coli has been observed for some polycations. 42,46–49 This reflects differences in the cell envelope structures of these bacteria, and highlights a possibility that cationic amphiphiles not active against Gram-negative and Gram-positive species may be highly active against Mtb .…”

“…39,40 H. Chen et al, in their review, have pointed to the mycobacterial membrane as a novel target for anti-tuberculosis drugs, such as cationic amphiphiles. 39 Low-molecular-weight cationic amphiphiles, 41 cationic dendrimers, 42 AMPs, 43,44 cationic polymers, 33,[45][46][47][48] and gold nanoparticles coated with polycations, 49 highly active against mycobacteria, have been reported to date. Most of those studies were performed on Mtb and Mycobacterium smegmatis (Mms), which is frequently employed as an avirulent and fast-growing model organism for Mtb, especially in mechanistic studies.…”

Engineered phosphorus dendrimers as powerful non-viral nanoplatforms for gene delivery: a great hope for the future of cancer therapeutics

“…Some examples were emphasized, except for PAMAM and phosphorus dendrimers. Regarding the phosphorus dendrimer types, the main therapeutic domains developed by Majoral et al are as follows: anti-inflammatory [ 23 ], anti-tuberculosis [ 24 ], anti-Alzheimer’s disease [ 25 ], anti-prion [ 26 ], and anti-cancer [ 22 , 27 ]. The theranostic realm in oncology has also been developed using phosphorus dendrimers and dendrons [ 28 ].…”