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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.

SUBMITTER: Ahmed S

PROVIDER: S-EPMC7653040 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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

Ahmed Shamim S Sony Sabrina Amita SA Chowdhury Md Belal MB Ullah Md Mahib MM Paul Shatabdi S Hossain Tanvir T

Scientific reports 20201109 1

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 affini ...[more]

PMID: 33168871

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Project description:Apramycin is an aminoglycoside antibiotic with the potential to be developed to combat multidrug-resistant pathogens. Its unique structure evades the clinically widespread mechanisms of aminoglycoside resistance that currently compromise the efficacy of other members in this drug class. Of the aminoglycoside-modifying enzymes that chemically alter these antibiotics, only AAC(3)-IVa has been demonstrated to confer resistance to apramycin through N-acetylation. Knowledge of other modification mechanisms is important to successfully develop apramycin for clinical use. Here, we show that ApmA is structurally unique among the previously described aminoglycoside-modifying enzymes and capable of conferring a high level of resistance to apramycin. In vitro experiments indicated ApmA to be an N-acetyltransferase, but in contrast to AAC(3)-IVa, ApmA has a unique regiospecificity of the acetyl transfer to the N2' position of apramycin. Crystallographic analysis of ApmA conclusively showed that this enzyme is an acetyltransferase from the left-handed β-helix protein superfamily (LβH) with a conserved active site architecture. The success of apramycin will be dependent on consideration of the impact of this potential form of clinical resistance.IMPORTANCE Apramycin is an aminoglycoside antibiotic that has been traditionally used in veterinary medicine. Recently, it has become an attractive candidate to repurpose in the fight against multidrug-resistant pathogens prioritized by the World Health Organization. Its atypical structure circumvents most of the clinically relevant mechanisms of resistance that impact this class of antibiotics. Prior to repurposing apramycin, it is important to understand the resistance mechanisms that could be a liability. Our study characterizes the most recently identified apramycin resistance element, apmA We show ApmA does not belong to the protein families typically associated with aminoglycoside resistance and is responsible for modifying a different site on the molecule. The data presented will be critical in the development of apramycin derivatives that will evade apmA in the event it becomes prevalent in the clinic.

Dataset Information

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

Publications

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

Similar Datasets

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