Aranorosin circumvents arbekacin-resistance in MRSA by inhibiting the bifunctional enzyme AAC(6′)/APH(2″)

Suga, Tetsuya; Ishii, Takahiro; Iwatsuki, Masato; Yamamoto, Tsuyoshi; Nonaka, Kenichi; Masuma, Rokuro; Matsui, Hidehito; Hanaki, Hideaki; Ōmura, Satoshi; Shiomi, Kazuro

doi:10.1038/ja.2012.53

Cited by 16 publications

(19 citation statements)

References 12 publications

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“…These include the APH(3')-IIIa inhibitor ankyrin repeat protein, 25, 26 the APH(2")-IVa inhibitor quercetin, 27 the APH(9)-Ia inhibitor CKI-7, which was co-crystallized with APH(3')-IIIa, 28 and the bifunctional enzyme AAC(6')-Ie/APH(2")-Ia inhibitor aranosin. 29 The 3-(dimethylamino)propylamine moiety was also found to be an essential scaffold for ANT(2")-Ia and APH(3')-IIIa inhibitors. 30 …”

Section: Introductionmentioning

confidence: 99%

New trends in the use of aminoglycosides

Fosso

2014

Med. Chem. Commun.

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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Section: Introductionmentioning

confidence: 99%

New trends in the use of aminoglycosides

Fosso

2014

Med. Chem. Commun.

100

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“…The World Health Organization recognizes antibiotic resistance as a serious threat to human health [10]. The global crisis of antibiotic resistance has spread rapidly over the last several decades, with multidrug-resistant MRSA as a major cause of serious infections in the United States [11,12,13,14,15].…”

Section: Introductionmentioning

confidence: 99%

Marinopyrrole Derivatives as Potential Antibiotic Agents against Methicillin-Resistant Staphylococcus aureus (III)

et al. 2014

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The marine natural product, marinopyrrole A (1), was previously shown to have significant antibiotic activity against Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). Although compound (1) exhibits a significant reduction in MRSA activity in the presence of human serum, we have identified key modifications that partially restore activity. We previously reported our discovery of a chloro-derivative of marinopyrrole A (1a) featuring a 2–4 fold improved minimum inhibitory concentration (MIC) against MRSA, significantly less susceptibility to serum inhibition and rapid and concentration-dependent killing of MRSA. Here, we report a novel fluoro-derivative of marinopyrrole A (1e) showing an improved profile of potency, less susceptibility to serum inhibition, as well as rapid and concentration-dependent killing of MRSA.

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“…Finally, the natural product aranorosin was found to be an inhibitor of the bifunctional AAC(6′)-Ie/APH(2″)-Ia enzyme, and its combination with the aminoglycoside arbekacin was shown to stop the growth of a methicillin-resistant Staphylococcus aureus strain. 24 …”

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confidence: 99%

Potent Inhibitors of Acetyltransferase Eis Overcome Kanamycin Resistance in Mycobacterium tuberculosis

et al. 2016

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A major cause of tuberculosis (TB) resistance to the aminoglycoside kanamycin (KAN) is the Mycobacterium tuberculosis (Mtb) acetyltransferase Eis. Upregulation of this enzyme is responsible for inactivation of KAN through acetylation of its amino groups. A 123 000-compound high-throughput screen (HTS) yielded several small-molecule Eis inhibitors that share an isothiazole S,S-dioxide heterocyclic core. These were investigated for their structure–activity relationships. Crystal structures of Eis in complex with two potent inhibitors show that these molecules are bound in the conformationally adaptable aminoglycoside binding site of the enzyme, thereby obstructing binding of KAN for acetylation. Importantly, we demonstrate that several Eis inhibitors, when used in combination with KAN against resistant Mtb, efficiently overcome KAN resistance. This approach paves the way toward development of novel combination therapies against aminoglycoside-resistant TB.

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Aranorosin circumvents arbekacin-resistance in MRSA by inhibiting the bifunctional enzyme AAC(6′)/APH(2″)

Cited by 16 publications

References 12 publications

New trends in the use of aminoglycosides

New trends in the use of aminoglycosides

Marinopyrrole Derivatives as Potential Antibiotic Agents against Methicillin-Resistant Staphylococcus aureus (III)

Potent Inhibitors of Acetyltransferase Eis Overcome Kanamycin Resistance in Mycobacterium tuberculosis

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