Aminoglycoside resistance profile and structural architecture of the aminoglycoside acetyltransferase AAC(6’)-Im

Authors:

Clyde A. Smith1, Monolekha Bhattacharya2, Marta Toth2, Nichole K. Stewart2 and Sergei B. Vakulenko2

doi: 10.15698/mic2017.12.602
Volume 4, pp. 402 to 410, published 09/11/2017.

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Affiliations:

1 Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, Menlo Park, CA 94025, USA.

2 Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA.

 

Keywords: 

antibiotic resistance, aminoglycosides, acetyltransferase, crystal structure.

Corresponding Author(s):

Clyde A. Smith, Stanford Synchrotron Radiation Lightsource, Stanford University, 2575 Sand Hill Rd, Menlo Park, CA 94025; Phone: (650) 926-8544; Fax: (650) 926-3292; csmith@slac.stanford.edu Sergei Vakulenko, Department of Chemistry and Biochemistry, University of Notre Dame, 340D McCourtney Hall, Notre Dame, IN, 46556; Phone: (574) 631-2935; Fax: (574) 631-6652; svakulen@nd.edu

Conflict of interest statement:

The authors declare no conflict of interest.

Please cite this article as:

Clyde A. Smith, Monolekha Bhattacharya, Marta Toth, Nichole K. Stewart and Sergei B. Vakulenko (2017). Aminoglycoside resistance profile and structural architecture of the aminoglycoside acetyltransferase AAC(6’)-Im. Microbial Cell 4(12): 402-410. doi: 10.15698/mic2017.12.602

© 2017 Smith et al. This is an open-access article released under the terms of the Creative Commons Attribution (CC BY) license, which allows the unrestricted use, distribution, and reproduction in any medium, provided the original author and source are acknowledged.

Abstract:

Aminoglycoside 6’-acetyltransferase-Im (AAC(6’)-Im) is the closest monofunctional homolog of the AAC(6’)-Ie acetyltransferase of the bifunctional enzyme AAC(6’)-Ie/APH(2”)-Ia. The AAC(6’)-Im acetyltransferase confers 4- to 64-fold higher MICs to 4,6-disubstituted aminoglycosides and the 4,5-disubstituted aminoglycoside neomycin than AAC(6’)-Ie, yet unlike AAC(6’)-Ie, the AAC(6’)-Im enzyme does not confer resistance to the atypical aminoglycoside fortimicin. The structure of the kanamycin A complex of AAC(6’)-Im shows that the substrate binds in a shallow positively-charged pocket, with the N6’ amino group positioned appropriately for an efficient nucleophilic attack on an acetyl-CoA cofactor. The AAC(6’)-Ie enzyme binds kanamycin A in a sufficiently different manner to position the N6’ group less efficiently, thereby reducing the activity of this enzyme towards the 4,6-disubstituted aminoglycosides. Conversely, docking studies with fortimicin in both acetyltransferases suggest that the atypical aminoglycoside might bind less productively in AAC(6’)-Im, thus explaining the lack of resistance to this molecule.