Identification and Characterization of Inhibitors of the Aminoglycoside Resistance Acetyltransferase Eis from <i>Mycobacterium tuberculosis</i>

Green, Keith D.; Chen, Wenjing; Garneau‐Tsodikova, Sylvie

doi:10.1002/cmdc.201100332

Cited by 57 publications

(103 citation statements)

References 37 publications

(32 reference statements)

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“…Unlike other AACs, which are regiospecific, the newly discovered enhanced intracellular survival (Eis) is a versatile enzyme that can acetylate different amine positions of AGs. 13–22 …”

Section: Introductionmentioning

confidence: 99%

New trends in the use of aminoglycosides

Fosso

2014

Med. Chem. Commun.

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100

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Despite their inherent toxicity and the acquired bacterial resistance that continuously threaten their long-term clinical use, aminoglycosides (AGs) still remain valuable components of the antibiotic armamentarium. Recent literature shows that the AGs’ role has been further expanded as multi-tasking players in different areas of study. This review aims at presenting some of the new trends observed in the use of AGs in the past decade, along with the current understanding of their mechanisms of action in various bacterial and eukaryotic cellular processes.

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“…Unlike other AACs, which are regiospecific, the newly discovered enhanced intracellular survival (Eis) is a versatile enzyme that can acetylate different amine positions of AGs. 13–22 …”

Section: Introductionmentioning

confidence: 99%

New trends in the use of aminoglycosides

Fosso

2014

Med. Chem. Commun.

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100

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“…Most commonly, small organic molecules have been explored for this purpose. For example, in silico and high-throughput screening was used to identify small organic molecules capable of inhibiting AAC(6=)-Ib (11) and Eis (12), respectively. Traditional synthesis was utilized to generate a library of 45 noncarbohydrate molecules containing a 1,3-diamine scaffold commonly found in AGs, which were found to be competitive inhibitors of APH(3=)-IIIa (13).…”

mentioning

confidence: 99%

Inhibition of Aminoglycoside Acetyltransferase Resistance Enzymes by Metal Salts

Green

Johnson

2015

Antimicrob Agents Chemother

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Aminoglycosides (AGs) are clinically relevant antibiotics used to treat infections caused by both Gram-negative and Gram-positive bacteria, as well as Mycobacteria. As with all current antibacterial agents, resistance to AGs is an increasing problem. The most common mechanism of resistance to AGs is the presence of AG-modifying enzymes (AMEs) in bacterial cells, with AG acetyltransferases (AACs) being the most prevalent. Recently, it was discovered that Zn 2؉ metal ions displayed an inhibitory effect on the resistance enzyme AAC(6=)-Ib in Acinetobacter baumannii and Escherichia coli. A minoglycosides (AGs) are broad-spectrum bactericidal antibiotics that are used clinically for the treatment of serious bacterial infections (1, 2). These antibiotics were originally isolated from Streptomyces and Micromonospora (3) and display activity against Gram-positive bacteria, aerobic Gram-negative pathogenic bacteria, and Mycobacteria. Since the discovery of streptomycin, the first-in-class AG isolated, many AGs have been discovered and developed with improved efficacy. This property has kept them clinically relevant despite their inherent oto-and nephrotoxicity. Currently, amikacin (AMK), gentamicin (GEN), and tobramycin (TOB) are the most commonly prescribed AGs for systemic administration in the United States against bacterial infections (see Fig. S1 in the supplemental material) (4). Another AG, kanamycin A (KAN), is also used systemically but only to treat resistant strains of Mycobacterium tuberculosis in patients who show no response to first-line antituberculosis treatments. Other AGs, such as neomycin B (NEO), are found in antibiotic ointment formulations for topical use (5).The increased importance and popularity of AGs have, unfortunately, led to lapses in antimicrobial stewardship. This has accelerated the development of resistance against AGs and reduced the effective agents available for combating ever-evolving pathogens. The most common mechanism of bacterial resistance to AGs is the acquisition of AG-modifying enzymes (AMEs) (6, 7). Based on the reactions that they catalyze, AMEs can be classified as AG N-acetyltransferases (AACs), AG O-phosphotransferases (APHs), or AG O-nucleotidyltransferases (ANTs), among which AACs are responsible for the majority of resistant infections. AACs modify AG substrates and disrupt their binding to the ribosome by transferring the acetyl group from acetyl coenzyme A (AcCoA) onto amine moieties of the AG scaffolds. Although most AACs are regiospecific and modify only a single amino group, the unique enhanced intracellular survival (Eis) protein upregulated in resistant M. tuberculosis strains is capable of acetylating AG substrates at several different positions (8)(9)(10).In an effort to overcome bacterial resistance, a large amount of time and money has been invested toward the development of inhibitors of these resistance enzymes. Most commonly, small organic molecules have been explored for this purpose. For example, in silico and high-throughput screening was used to ide...

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“…All three aminoglycosides and a truncated aminoglycoside–coenzyme A bisubstrate analogue described by Gao et al 36 showed the highest binding affinity. Compound 1 exhibited the next highest affinity binding followed by chlorhexidine and several small molecules previously identified by Green et al 37 as inhibitors of the acetyltransferase Eis from Mycobacterium tuberculosis . These results validated the ability of the Glide docking program to identify potential compounds that have high binding affinity to the AAC(6’)-Ib region selected.…”

Section: Resultsmentioning

confidence: 88%

“…Enzymatic activity of AAC(6’)-Ib was determined using a method based on monitoring the increase in OD 412 after 5,5’-dithiobis(2-nitrobenzoic acid) (DTNB) reacts with the CoA–SH released from acetyl CoA after acetylation of the aminoglycoside 37 as described before 21 . Briefly, the standard reaction mix contained acetyl CoA (150 µM), DTNB (0.2 mM), Tris-HCl pH 7.5 buffer (20 mM), and kanamycin A (18 µM), and when needed the testing compound at the indicated concentrations was incubated for 10 minutes at room temperature followed by addition of the enzyme.…”

Section: Methodsmentioning

confidence: 99%

“…Early efforts permitted to identify a multisubstrate inhibitor of an AAC(3’) 35 . Bisubstrate and bisubstrate-like inhibitors were later designed to target AAC(6’) enzymes but most showed low efficacy in vivo 24, 26–30, 34, 36, 37 . Antimicrobial peptides were also tested as inhibitors of aminoglycoside acetyltransefrases as well as aminoglycoside phosphotransferases 31 .…”

Section: Introductionmentioning

confidence: 99%

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Identification of an inhibitor of the aminoglycoside 6′-N-acetyltransferase type Ib [AAC(6′)-Ib] by glide molecular docking

et al. 2016

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The aminoglycoside 6’-N-acetyltransferase type Ib, AAC(6’)-Ib, confers resistance to clinically relevant aminoglycosides and is the most widely distributed enzyme among AAC(6’)-I-producing Gram-negative pathogens. An alternative to counter the action of this enzyme is the development of inhibitors. Glide is a computational strategy for rapidly docking ligands to protein sites and estimating their binding affinities. We docked a collection of 280,000 compounds from 7 sub-libraries of the Chembridge library as ligands to the aminoglycoside binding site of AAC(6’)-Ib. We identified a compound, 1-[3-(2-aminoethyl)benzyl]-3-(piperidin-1-ylmethyl)pyrrolidin-3-ol (compound 1), that inhibited the acetylation of aminoglycosides in vitro with IC50 values of 39.7 and 34.9 µM when the aminoglycoside substrates assayed were kanamycin A or amikacin, respectively. The growth of an amikacin-resistant Acinetobacter baumannii clinical strain was inhibited in the presence of a combination of amikacin and compound 1.

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Identification and Characterization of Inhibitors of the Aminoglycoside Resistance Acetyltransferase Eis from Mycobacterium tuberculosis

Cited by 57 publications

References 37 publications

New trends in the use of aminoglycosides

New trends in the use of aminoglycosides

Inhibition of Aminoglycoside Acetyltransferase Resistance Enzymes by Metal Salts

Identification of an inhibitor of the aminoglycoside 6′-N-acetyltransferase type Ib [AAC(6′)-Ib] by glide molecular docking

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