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

Abstract

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.

Amikacin potentiator activity of zinc complexed to a pyrithione derivative with enhanced solubility

“…In our quest to identify compounds that inhibit the AAC(6′)-Ib amikacin-disabling action, we recently found that various cations effectively interfere with the enzymatic inactivation 11,12,[19][20][21] . In the case of Zn 2+ , the concentrations needed to inhibit growth of amikacin-resistant cells in the presence of the antibiotic are significantly reduced if the cation is added to the growth media in complex with ionophores [11][12][13][20][21][22] . A very effective complex to reduce amikacin resistance levels in various bacteria is ZnPT, a compound already being researched and repurposed for cancer treatments and that has low toxicity when tested on mice 23,24 .…”

Zinc: Multidimensional Effects on Living Organisms

“…Recent studies to identify inhibitors of this resistance mechanism showed that zinc interferes with enzymatic inactivation by acetylation catalyzed by the aminoglycoside 6’- N -acetyltransferase type Ib (AAC(6’)-Ib) and others [ 68 , 193 , 196 , 197 , 198 ]. The initial experiments showed that zinc ions very efficiently inhibited AAC(6’)-Ib-mediated acetylation of aminoglycosides in vitro [ 68 ].…”

Zinc: Multidimensional Effects on Living Organisms

“…Recent studies to identify inhibitors of this resistance mechanism showed that zinc interferes with enzymatic inactivation by acetylation catalyzed by the aminoglycoside 6'-Nacetyltransferase type Ib [AAC(6')-Ib] and others [72,202,[205][206][207]. The initial experiments showed that zinc ions very efficiently inhibited AAC(6')-Ib-mediated acetylation of aminoglycosides in vitro [72].…”