Abstract
Effective treatment of tuberculosis is frequently hindered by the emerging antimicrobial resistance of Mycobacterium tuberculosis. The present study evaluates monocyclic β-lactam compounds targeting the mycobacterial cell wall remodeling. Novel N-thio-β-lactams were designed, synthesized, and characterized on the L,D-transpeptidase-2, a validated target in M. tuberculosis. The candidates were evaluated in biochemical assays identifying five compounds presenting target-specific kinetic constants equal or superior to meropenem, a carbapenem currently considered for tuberculosis therapy. Mass spectrometry in line with the crystal structures of five target-ligand complexes revealed that the N-thio-β-lactams act via an unconventional mode of adduct formation, transferring the thio-residues from the lactam ring to the active-site cysteine of LdtMt2. The resulting stable adducts lead to a long-term inactivation of the target protein. Finally, the candidates were evaluated invitro against a drug-susceptible and multidrug-resistant clinical isolates of M. tuberculosis, confirming the antimycobacterial effect of these novel compounds.
Highlights
The mycobacterial cell envelope is more complex than the cell wall of Gram-positive or Gram-negative bacteria and is an established target for antibiotics including specific antitubercular agents which act by interfering with cell wall stability and maintenance
Effective treatment of tuberculosis is frequently hindered by the emerging antimicrobial resistance of Mycobacterium tuberculosis
The present study evaluates monocyclic b-lactam compounds targeting the mycobacterial cell wall remodeling
Summary
The mycobacterial cell envelope is more complex than the cell wall of Gram-positive or Gram-negative bacteria and is an established target for antibiotics including specific antitubercular agents which act by interfering with cell wall stability and maintenance. This multilayered structure is in part responsible for the increased stress tolerance and for the relatively low permeability to antibiotics, a characteristic of M. tuberculosis (Dulberger et al, 2020; Jankute et al, 2015). In addition to this protective barrier the expression of efflux pumps, b-lactamases (BLA), and modified peptidoglycan structure contribute to the increased antibiotic tolerance of this pathogen (Wivagg et al, 2014)
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