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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.

In this study, we have designed and synthesized pyrazoline analogues that partially mimic the structure of mycobactin, to address the requirement of novel therapeutics to tackle the emerging global challenge of antimicrobial resistance (AMR). Our investigation resulted in the identification of novel lead compounds 44 and 49 as potential mycobactin biosynthesis inhibitors against mycobacteria. Moreover, candidates efficiently eradicated intracellularly surviving mycobacteria. Thermofluorimetric analysis and molecular dynamics simulations suggested that compounds 44 and 49 bind to salicyl-AMP ligase (MbtA), a key enzyme in the mycobactin biosynthetic pathway. To the best of our knowledge, these are the first rationally designed mycobactin inhibitors to demonstrate an excellent in vivo pharmacokinetic profile. In addition, these compounds also exhibited more potent whole-cell efflux pump inhibition than known efflux pump inhibitors verapamil and chlorpromazine. Results from this study pave the way for the development of 3-(2-hydroxyphenyl)-5-(aryl)-pyrazolines as a new weapon against superbug-associated AMR challenges.