Repurposing Azoles to Resolve Serotogenic Toxicity Associated with Linezolid to Combat Multidrug-Resistant Tuberculosis

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 mu M. Additionally, Clotrimazole exhibited reasonable MIC50 values of 0.17 mu M, 1.72 mu M, 1.53 mu M, and 5.07 mu M 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.