Structure-based design of haloperidol analogues as inhibitors of acetyltransferase Eis from: Mycobacterium tuberculosis to overcome kanamycin resistance

Ankita Punetha, Keith D. Green, Atefeh Garzan, Nishad Thamban Chandrika, Melisa J. Willby, Allan H. Pang, Caixia Hou, Selina Y.L. Holbrook, Kyle Krieger, James E. Posey, Tanya Parish, Oleg V. Tsodikov, Sylvie Garneau-Tsodikova

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9 Scopus citations


Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is a deadly bacterial disease. Drug-resistant strains of Mtb make eradication of TB a daunting task. Overexpression of the enhanced intracellular survival (Eis) protein by Mtb confers resistance to the second-line antibiotic kanamycin (KAN). Eis is an acetyltransferase that acetylates KAN, inactivating its antimicrobial function. Development of Eis inhibitors as KAN adjuvant therapeutics is an attractive path to forestall and overcome KAN resistance. We discovered that an antipsychotic drug, haloperidol (HPD, 1), was a potent Eis inhibitor with IC50 = 0.39 ± 0.08 μM. We determined the crystal structure of the Eis-haloperidol (1) complex, which guided synthesis of 34 analogues. The structure-activity relationship study showed that in addition to haloperidol (1), eight analogues, some of which were smaller than 1, potently inhibited Eis (IC50 ≤ 1 μM). Crystal structures of Eis in complexes with three potent analogues and droperidol (DPD), an antiemetic and antipsychotic, were determined. Three compounds partially restored KAN sensitivity of a KAN-resistant Mtb strain K204 overexpressing Eis. The Eis inhibitors generally did not exhibit cytotoxicity against mammalian cells. All tested compounds were modestly metabolically stable in human liver microsomes, exhibiting 30-60% metabolism over the course of the assay. While direct repurposing of haloperidol as an anti-TB agent is unlikely due to its neurotoxicity, this study reveals potential approaches to modifying this chemical scaffold to minimize toxicity and improve metabolic stability, while preserving potent Eis inhibition.

Original languageEnglish
Pages (from-to)1894-1909
Number of pages16
JournalRSC Medicinal Chemistry
Issue number11
StatePublished - Nov 2021

Bibliographical note

Publisher Copyright:
© The Royal Society of Chemistry.

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry


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