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

• 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: England Nature Publishing Group 09.11.2020; Nature Publishing Group UK
• Subjects: Acetyltransferase; Acetyltransferases - antagonists & inhibitors; Acetyltransferases - chemistry; Adjuvants; Affinity; Amikacin; Aminoglycoside antibiotics; Antibacterial activity; Antibiotics; Bacterial Proteins - antagonists & inhibitors; Bacterial Proteins - chemistry; Drug Resistance, Bacterial; Enzymatic activity; Enzymes; Escherichia coli - enzymology; Gentamicin; Gram-negative bacteria; Kanamycin; Klebsiella pneumoniae - enzymology; Molecular Docking Simulation; N-Acetyltransferase; Shigella sonnei - enzymology; Vitamin D; Vitamin E; Vitamin K; Vitamins; Zinc pyrithione
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-76355-0

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.