Analogues of the Herbicide, N-Hydroxy-N-isopropyloxamate, Inhibit Mycobacterium tuberculosis Ketol-Acid Reductoisomerase and Their Prodrugs Are Promising Anti-TB Drug Leads.
Ajit KandaleKhushboo PatelWaleed M HusseinShun Jie WunShan ZhengLendl TanNicholas P WestGerhard SchenkLuke W GuddatRoss P McGearyPublished in: Journal of medicinal chemistry (2021)
New drugs to treat tuberculosis (TB) are urgently needed to combat the increase in resistance observed among the current first-line and second-line treatments. Here, we propose ketol-acid reductoisomerase (KARI) as a target for anti-TB drug discovery. Twenty-two analogues of IpOHA, an inhibitor of plant KARI, were evaluated as antimycobacterial agents. The strongest inhibitor of Mycobacterium tuberculosis (Mt) KARI has a Ki value of 19.7 nM, fivefold more potent than IpOHA (Ki = 97.7 nM). This and four other potent analogues are slow- and tight-binding inhibitors of MtKARI. Three compounds were cocrystallized with Staphylococcus aureus KARI and yielded crystals that diffracted to 1.6-2.0 Å resolution. Prodrugs of these compounds possess antimycobacterial activity against H37Rv, a virulent strain of human TB, with the most active compound having an MIC90 of 2.32 ± 0.04 μM. This compound demonstrates a very favorable selectivity window and represents a highly promising lead as an anti-TB agent.
Keyphrases
- mycobacterium tuberculosis
- pulmonary tuberculosis
- drug discovery
- staphylococcus aureus
- molecular docking
- endothelial cells
- photodynamic therapy
- neoadjuvant chemotherapy
- squamous cell carcinoma
- structure activity relationship
- blood brain barrier
- emergency department
- escherichia coli
- single molecule
- lymph node
- cystic fibrosis
- transcription factor
- molecular dynamics simulations
- pluripotent stem cells
- biofilm formation
- dna binding
- rectal cancer