Antibiotic resistance is a global health problem. New antibiotics acting on new targets are needed to keep pace with resistance. Mycobacterium tuberculosis (Mtb), which causes the TB infection, exports glutamine synthetase (GS) outside the cell during host macrophage infection. Thus, MtGS could be a promising anti-TB target that circumvents the need to penetrate the cell envelope. The 3-hydroxy-beta-lactam (3-HβL) group has been shown to be a potent GS transition state mimic. Novel methods are required to synthesize 3-HβL containing inhibitors including the natural inhibitor tabtoxinine-beta-lactam (TβL) produced by Pseudomonas syringae. The TβL scaffold can be constructed by performing an optimized Grubbs cross-metathesis of vinylogous C3-substituted 3-HβL with vinyl glycine. The trans-olefin resulting from the cross-metathesis allows for further synthetic modification. Additionally, the solid-state peptide synthesis approach could be utilized for synthesizing di- and tri-peptide prodrugs of TβL and related GS inhibitors. These pro-drugs were investigated as anti-TB agents to selectively target cytoplasmic over extracellular GS by exploiting conserved peptide transporters for cell entry. The GS inhibitors and prodrugs can be optimized as potent anti-TB agents for use in combination therapy to provide synergistic growth inhibitory activity against resistant strains

Grubbs cross metathesis route to improve 3-hydroxy-β-lactam inhibitors of glutamine synthetase

ACS Spring Meeting 2021

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