ABSTRACTKlebsiella pneumoniae is a leading cause of both hospital- and community-acquired pneumonia. Nanomaterials have the potential to deliver antibiotics directly to sites of infection with improved pharmacokinetics and to avoid development of antimicrobial resistance. We previously demonstrated the use of alveolar macrophage (AM)-targeted polymeric prodrugs to prevent pneumonia in murine models caused by the facultative intracellular pathogens Francisella novicida and Burkholderia pseudomallei. These fully synthetic mannose-tagged polymers engage with AM mannose receptors, permitting uptake and triggering intracellular ciprofloxacin release. Here we show that the AMs can also serve as a reservoir for releasing antibiotics to treat infections caused by a primarily extracellular bacterium. Aerosolized ciprofloxacin polymeric prodrugs significantly improved survival in a murine model of K. pneumoniae pneumonia, reduced lung bacterial burden, lessened extent of lung injury, and prevented excessive neutrophilic inflammation.

The human gut microbiome has been increasingly recognized as a metabolic compartment that influences health and therapeutic responses. While recent studies have cataloged diverse sets of drug biotransformation reactions as a result of microbial metabolism, the pharmacological relevance of the resulting drug metabolites remains mostly uncharacterized. We investigated whether certain microbial drug metabolites can act as functional prodrugs. By systematically mining 871 putative drug metabolites produced by gut bacteria, we identified microbial drug metabolites with key physicochemical properties of prodrugs. Using bacterial culturing, a genetic gain-of-function screen coupled to mass spectrometry and comparative genomics, we uncover that Bacteroidota bacteria encode conserved methyltransferases that can generate prodrugs through carboxyl methylation. As a case in point, we demonstrate that bezafibrate gets converted to a prodrug by a distinct bacterial enzyme, increasing epithelial drug permeability in vitro and systemic drug exposure in vivo in a gnotobiotic mouse model. Additionally, we tested 170 structurally and clinically diverse drugs, and demonstrate that microbial drug-to-prodrug conversion is a common result of gut bacterial drug biotransformation. Altogether, our findings suggest a novel mechanism of how the gut microbiota influences an individual's pharmacokinetics, and may generally cause interpersonal differences in microbiota-host metabolic interactions.

We present a new method to obtain tertiary amine-based prodrugs with dual functionality, enabling (i) signal-triggered drug activation and (ii) covalent incorporation in polymer materials through a cl...

Novel Pt(IV) complexes conjugated with the kinase inhibitors crizotinib or ceritinib were synthesized and assessed for anticancer activity. Cisplatin-derived derivatives bearing phenylbutyrate and eit...

Phosphorus(v) stereocenters play a crucial role in the therapeutic strategies for severe diseases, including viral infections, chronic conditions, and rare genetic disorders. These diseases often involve gene-related pathologies or arise from genetic mutations that affect intracellular metabolic processes. P

A series of thiophene-expanded tricyclic nucleosides featuring modifications not previously investigated, including sugar and nucleobase modifications, were synthesized as potential antiviral therapeu...

In the ever-evolving battle against cancer, researchers continue to seek smarter, more targeted strategies to harness the body’s own immune system. A groundbreaking development unveiled by Hsu, Tang, Mendes, and colleagues showcases a next-generation approach that combines chemical ingenuity with immunotherapy: the creation of a tumour-specific STING agonist through a sophisticated two-component prodrug system. This ingenious design promises to overcome longstanding challenges in selectively activating the immune response directly within tumour tissues, sparing healthy areas and reducing systemic toxicity.

Antibody–drug conjugates (ADCs) are promising targeted cancer therapies but have a limited payload scope. Antibody–bottlebrush prodrug conjugates offer modular synthesis and high drug-to-antibody rati...

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This is a summary of: Liu, B. et al. Antibody–bottlebrush prodrug conjugates for targeted cancer therapy. Nat. Biotechnol. (2025). Source link

Researchers at National Taiwan University have discovered a versatile enzyme from Bacillus subtilis that efficiently attaches phosphate groups to a wide variety of phenolic molecules, offering a sustainable and precise alternative to conventional chemical phosphorylation methods.