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) H37Rv strain compared to
Linezolid, with a minimal inhibitory concentration (MIC) of 2.26 μM. Additionally,
Clotrimazole exhibited reasonable MIC50 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.