Probing the Robustness of Inhibitors of Tuberculosis Aminoglycoside Resistance Enzyme Eis by Mutagenesis

Journal Article · Wed Aug 21 00:00:00 EDT 2019 · ACS Infectious Diseases

DOI:https://doi.org/10.1021/acsinfecdis.9b00228· OSTI ID:1577149

Green, Keith D. ^[1]; Punetha, Ankita ^[1]; Hou, Caixia ^[1]; Garneau-Tsodikova, Sylvie ^[1]; Tsodikov, Oleg V. ^[1]

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1. Univ. of Kentucky, Lexington, KY (United States)

Every year, millions of people worldwide contract tuberculosis (TB), the deadliest infection. The spread of infections with drug-resistant strains of Mycobacterium tuberculosis (Mtb) that are refractory to treatment poses a major global challenge. A major cause of resistance to antitubercular drugs of last resort, aminoglycosides, is overexpression of the Eis (enhanced intracellular survival) enzyme of Mtb, which inactivates aminoglycosides by acetylating them. We showed previously that this inactivation of aminoglycosides could be overcome by our recently reported Eis inhibitors that are currently in development as potential aminoglycoside adjunctive therapeutics against drug-resistant TB. To interrogate the robustness of the Eis inhibitors, we investigated the enzymatic activity of Eis and its inhibition by Eis inhibitors from three different structural families for nine single-residue mutants of Eis, including those found in the clinic. Three engineered mutations of the substrate binding site, D26A, W36A, and F84A, abolished inhibitor binding while compromising Eis enzymatic activity 2- to 3-fold. All other Eis mutants, including clinically observed ones, were potently inhibited by at least one inhibitor. This study helps position us one step ahead of Mtb resistance to Eis inhibitors as they are being developed for TB therapy.

• Research Organization: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
• Sponsoring Organization: National Institutes of Health (NIH)
• OSTI ID: 1577149
• Journal Information: ACS Infectious Diseases, Journal Name: ACS Infectious Diseases Journal Issue: 10 Vol. 5; ISSN 2373-8227
• Publisher: American Chemical Society (ACS)
• Country of Publication: United States
• Language: ENGLISH

Related Subjects

60 APPLIED LIFE SCIENCES
acetylation
enzyme inhibitor
kanamycin
mutations
mycobacteria