# Synthesis and anti-mycobacterial activity of novel medium-chain β-lactone derivatives: a multi-target strategy to combat Mycobacterium abscessus

## TL;DR

Scientists created new β-lactone compounds that can inhibit the growth of drug-resistant mycobacteria like M. abscessus and M. tuberculosis, both inside and outside cells.

## Contribution

The study introduces novel β-lactone derivatives with multitarget activity against pathogenic mycobacteria and identifies potential therapeutic targets.

## Key findings

- VM025 and VM026 effectively inhibit intracellular M. abscessus growth with MIC50Raw comparable to imipenem.
- VM043 inhibits extracellular M. abscessus growth and targets multiple enzymes via chemoproteomics.
- The β-lactone derivatives are non-toxic to host macrophages.

## Abstract

The constant emergence of drug-resistant mycobacteria, together with the lack of new antibiotics entering the market, has become a global public health problem that threatens the effective treatment of infectious diseases. The development of single molecules targeting different proteins should significantly reduce the emergence of resistant strains, and therefore represent a promising strategy to overcome such an issue. In this challenging context, a new series of 30 lipophilic compounds based on the β-lactone-core has been synthesized by varying the nature of the substituents on the lactone ring. The evaluation of their antibacterial activity against M. tuberculosis and M. abscessus, two major pathogenic mycobacteria, highlighted potential candidates. The VM038, VM040 and VM045 were active only against M. tuberculosis, while VM025, VM026 and VM043 inhibited the growth of both M. tuberculosis and the S and R variants of M. abscessus. Competitive click chemistry activity-based protein profiling revealed several potential M. abscessus target enzymes of VM043, the best extracellular growth inhibitor. Finally, when tested against intracellular bacteria, although VM043 was found inactive, VM025 & VM026 proved to be potent and promising inhibitors of intramacrophagic M. abscessus growth with minimal inhibitory concentrations (MIC50Raw) comparable to the standard antibiotic imipenem. Overall, these results strengthen the added value of our VM β-lactone derivatives not only in the fight against pathogenic mycobacteria, leading to the arrest of M. abscessus and/or M. tuberculosis growth through multitarget enzyme inhibition, but also as efficient probes to identify novel potential therapeutic targets using chemoproteomics approaches.

Novel lipophilic β-lactone VM derivatives inhibit the extracellular and/or intracellular growth of M. abscessus, while being nontoxic to host macrophages.