Repurposing Azoles to Resolve Serotogenic Toxicity Associated with Linezolid to Combat Multidrug-Resistant Tuberculosis.
Rukaiyya T GiraseIqrar AhmadJong Min OhHoon KimBijo MathewSiva K VagoluTone TønjumNisheeth C DesaiDharmarajan SriramJyothi KumariHarun M PatelPublished in: ACS medicinal chemistry letters (2023)
Serotogenic toxicity is a major hurdle associated with Linezolid in the treatment of drug-resistant tuberculosis (TB) due to the inhibition of monoamine oxidase (MAO) enzymes. Azole compounds demonstrate structural similarities to the recognized anti-TB drug Linezolid, making them intriguing candidates for repurposing. Therefore, we have repurposed azoles (Posaconazole, Itraconazole, Miconazole, and Clotrimazole) for the treatment of drug-resistant TB with the anticipation of their selectivity in sparing the MAO enzyme. The results of repurposing revealed that Clotrimazole showed equipotent activity against the Mycobacterium tuberculosis ( Mtb ) H 37 Rv strain compared to Linezolid, with a minimal inhibitory concentration (MIC) of 2.26 μM. Additionally, Clotrimazole exhibited reasonable MIC 50 values of 0.17 μM, 1.72 μM, 1.53 μM, and 5.07 μM against the inhA promoter+, katG+ , rpoB+ , and MDR clinical Mtb isolates, respectively, compared to Linezolid. Clotrimazole also exhibited 3.90-fold less inhibition of MAO-A and 50.35-fold less inhibition of MAO-B compared to Linezolid, suggesting a reduced serotonergic toxicity burden.
Keyphrases
- mycobacterium tuberculosis
- drug resistant
- multidrug resistant
- acinetobacter baumannii
- methicillin resistant staphylococcus aureus
- pulmonary tuberculosis
- gram negative
- klebsiella pneumoniae
- gene expression
- pseudomonas aeruginosa
- single cell
- staphylococcus aureus
- combination therapy
- human immunodeficiency virus
- cystic fibrosis
- hiv infected
- risk factors