Retention of antibiotic activity against resistant bacteria harbouring aminoglycoside-N-acetyltransferase enzyme by adjuvants: a combination of in-silico and in-vitro study

Interference with antibiotic activity and its inactivation by bacterial modifying enzymes is a prevailing mode of bacterial resistance to antibiotics. Aminoglycoside antibiotics become inactivated by aminoglycoside-6′-N-acetyltransferase-Ib [AAC(6′)-Ib] of gram-negative bacteria which transfers an a...

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Bibliographic Details
Published in:	Scientific reports Vol. 10; no. 1; p. 19381
Main Authors:	Ahmed, Shamim, Sony, Sabrina Amita, Chowdhury, Md. Belal, Ullah, Md. Mahib, Paul, Shatabdi, Hossain, Tanvir
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 09-11-2020 Nature Publishing Group
Subjects:	631/114/2248 631/326/22/1290 631/326/22/1434 Acetyltransferase Acetyltransferases - antagonists & inhibitors Acetyltransferases - chemistry Adjuvants Affinity Amikacin Aminoglycoside antibiotics Antibacterial activity Antibiotics Bacteria Bacterial Proteins - antagonists & inhibitors Bacterial Proteins - chemistry Drug Resistance, Bacterial E coli Enzymatic activity Enzymes Escherichia coli - enzymology Gentamicin Gram-negative bacteria Humanities and Social Sciences Inactivation Kanamycin Klebsiella pneumoniae - enzymology Molecular Docking Simulation multidisciplinary N-Acetyltransferase Science Science (multidisciplinary) Shigella sonnei - enzymology Vitamin D Vitamin E Vitamin K Vitamins Zinc pyrithione
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Summary:	Interference with antibiotic activity and its inactivation by bacterial modifying enzymes is a prevailing mode of bacterial resistance to antibiotics. Aminoglycoside antibiotics become inactivated by aminoglycoside-6′-N-acetyltransferase-Ib [AAC(6′)-Ib] of gram-negative bacteria which transfers an acetyl group from acetyl-CoA to the antibiotic. The aim of the study was to disrupt the enzymatic activity of AAC(6′)-Ib by adjuvants and restore aminoglycoside activity as a result. The binding affinities of several vitamins and chemical compounds with AAC(6′)-Ib of Escherichia coli , Klebsiella pneumoniae , and Shigella sonnei were determined by molecular docking method to screen potential adjuvants. Adjuvants having higher binding affinity with target enzymes were further analyzed in-vitro to assess their impact on bacterial growth and bacterial modifying enzyme AAC(6′)-Ib activity. Four compounds—zinc pyrithione (ZnPT), vitamin D, vitamin E and vitamin K-exhibited higher binding affinity to AAC(6′)-Ib than the enzyme’s natural substrate acetyl-CoA. Combination of each of these adjuvants with three aminoglycoside antibiotics—amikacin, gentamicin and kanamycin—were found to significantly increase the antibacterial activity against the selected bacterial species as well as hampering the activity of AAC(6′)-Ib. The selection process of adjuvants and the use of those in combination with aminoglycoside antibiotics promises to be a novel area in overcoming bacterial resistance.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2045-2322 2045-2322
DOI:	10.1038/s41598-020-76355-0