Dual activity of low-molecular-weight polymeric β-cyclodextrins against tuberculosis

Tuberculosis remains the leading cause of death from infectious diseases. While effective therapies are available, their prolonged duration and severe adverse effects compromise patient adherence and promote antimicrobial resistance, highlighting the urgent need for innovative therapeutic approaches. We previously identified polymeric β-cyclodextrin (pβCD) as a promising drug delivery platform, possessing intrinsic antibacterial activity and serving as a carrier for the second-line drug ethionamide. Here, we investigated the biological properties of pβCD of different molecular weights. Strikingly, only the low-molecular-weight pβCD (LMW-pβCD) displayed antibacterial activity, in contrast to the high-molecular-weight one. Mechanistically, this activity was linked to the inhibition of Mycobacterium tuberculosis entry into macrophages through disruption of lipid rafts. Transcriptomic profiling further revealed that the LMW-pβCD also enhanced pro-inflammatory cytokine secretion, suggesting dual antimicrobial and immunomodulatory functions. Notably, linezolid, an important second-line anti-tuberculosis drug, was efficiently incorporated in pβCD, regardless of its molecular weight. These findings emphasize the critical importance of molecular weight in dictating pβCD bioactivity. Only LMW-pβCD combines antimicrobial and immunomodulatory activities with effective drug delivery, making it a promising candidate for the development of novel anti-tuberculosis therapies.