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

Rukaiyya T Girase; Iqrar Ahmad; Jong Min Oh; Hoon Kim; Bijo Mathew; Siva K Vagolu; Tone Tønjum; Nisheeth C Desai; Dharmarajan Sriram; Jyothi Kumari; Harun M Patel

doi:10.1021/acsmedchemlett.3c00406

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

ACS Med Chem Lett. 2023 Nov 1;14(12):1754-1759. doi: 10.1021/acsmedchemlett.3c00406. eCollection 2023 Dec 14.

Authors

Rukaiyya T Girase¹, Iqrar Ahmad¹, Jong Min Oh², Hoon Kim², Bijo Mathew³, Siva K Vagolu⁴, Tone Tønjum^{4

5}, Nisheeth C Desai⁶, Dharmarajan Sriram⁷, Jyothi Kumari⁷, Harun M Patel¹

Affiliations

¹ Department of Pharmaceutical Chemistry, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, Maharashtra India, 4254.
² Department of Pharmacy, and Research Institute of Life Pharmaceutical Sciences, Sunchon National University, Suncheon 57922, Republic of Korea.
³ Department of Pharmaceutical Chemistry, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, Kochi 690525, India.
⁴ Department of Microbiology, University of Oslo, N-0316 Oslo, Norway.
⁵ Department of Microbiology, Oslo University Hospital, N-0424 Oslo, Norway.
⁶ Division of Medicinal Chemistry, Department of Chemistry (DST-FIST Sponsored), Maharaja Krishnakumarsinhji Bhavnagar University, Mahatma Gandhi Campus, Bhavnagar 364 002, India.
⁷ Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet Mandal, R. R. District, Hyderabad 500078, India.

PMID: 38116435
PMCID: PMC10726462 (available on 2024-12-14)
DOI: 10.1021/acsmedchemlett.3c00406

Abstract

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.