rl-rl interactions stabilize PeptoMicelle-based formulations of Pretomanid derivatives leading to promising therapy against tuberculosis in zebrafish and mouse models

Tuberculosis is the deadliest bacterial disease globally, threatening the lives of millions every year. New anti-biotic therapies that can shorten the duration of treatment, improve cure rates, and impede the development of drug resistance are desperately needed. Here, we used polymeric micelles to encapsulate four second-generation derivatives of the antitubercular drug pretomanid that had previously displayed much better in vivo activity against Mycobacterium tuberculosis than pretomanid itself. Because these compounds were relatively hydrophobic and had limited bioavailability, we expected that their micellar formulations would overcome these limitations, reduce toxicities, and improve therapeutic outcomes. The polymeric micelles were based on polypept(o)ides (PeptoMicelles) and were stabilized in their hydrophobic core by rc-rc interactions, allowing the efficient encapsulation of aromatic pretomanid derivatives. The stability of these rc-rc-stabilized PeptoMicelles was demonstrated in water, blood plasma, and lung surfactant by fluorescence cross-correlation spectroscopy and was further supported by prolonged circulation times of several days in the vasculature of zebrafish larvae. The most efficacious PeptoMicelle formulation tested in the zebrafish larvae infection model almost completely eradicated the bacteria at non-toxic doses. This lead formulation was further assessed against Mycobacterium tuberculosis in the susceptible C3HeB/FeJ mouse model, which develops human-like necrotic granulomas. Following intravenous administration, the drug-loaded PeptoMicelles significantly reduced bacterial burden and inflammatory responses in the lungs and spleens of infected mice.

Automated summary

Tuberculosis is a deadly bacterial disease that threatens millions of lives each year. In this study, polymeric micelles were used to encapsulate four derivatives of the antitubercular drug pretomanid, which showed better in vivo activity against Mycobacterium tuberculosis. These micelles overcame the hydrophobicity and limited bioavailability of the compounds, reducing toxicities and improving therapeutic outcomes.