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Antimicrobial Agents and Chemotherapy, July 2009, p. 3049-3055, Vol. 53, No. 7
0066-4804/09/$08.00+0     doi:10.1128/AAC.00062-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Structural Basis of APH(3')-IIIa-Mediated Resistance to N1-Substituted Aminoglycoside Antibiotics{triangledown} ,{dagger}

Desiree H. Fong1 and Albert M. Berghuis1,2*

Department of Biochemistry, McGill University, Montreal, Quebec H3G 1Y6, Canada,1 Department of Microbiology & Immunology, McGill University, Montreal, Quebec H3A 2B4, Canada2

Received 15 January 2009/ Returned for modification 25 April 2009/ Accepted 1 May 2009

Butirosin is unique among the naturally occurring aminoglycosides, having a substituted amino group at position 1 (N1) of the 2-deoxystreptamine ring with an (S)-4-amino-2-hydroxybutyrate (AHB) group. While bacterial resistance to aminoglycosides can be ascribed chiefly to drug inactivation by plasmid-encoded aminoglycoside-modifying enzymes, the presence of an AHB group protects the aminoglycoside from binding to many resistance enzymes, and hence, the antibiotic retains its bactericidal properties. Consequently, several semisynthetic N1-substituted aminoglycosides, such as amikacin, isepamicin, and netilmicin, were developed. Unfortunately, butirosin, amikacin, and isepamicin are not resistant to inactivation by 3'-aminoglycoside O-phosphotransferase type IIIa [APH(3')-IIIa]. We report here the crystal structure of APH(3')-IIIa in complex with an ATP analog, AMPPNP [adenosine 5'-(β,{gamma}-imido)triphosphate], and butirosin A to 2.4-Å resolution. The structure shows that butirosin A binds to the enzyme in a manner analogous to other 4,5-disubstituted aminoglycosides, and the flexible antibiotic-binding loop is key to the accommodation of structurally diverse substrates. Based on the crystal structure, we have also constructed a model of APH(3')-IIIa in complex with amikacin, a commonly used semisynthetic N1-substituted 4,6-disubstituted aminoglycoside. Together, these results suggest a strategy to further derivatize the AHB group in order to generate new aminoglycoside derivatives that can elude inactivation by resistance enzymes while maintaining their ability to bind to the ribosomal A site.

* Corresponding author. Mailing address: Room 466, Bellini Pavilion, 3649 Promenade Sir William Osler, Montreal, Quebec H3G 0B1, Canada. Phone: (514) 398-8795. Fax: (514) 398-2983. E-mail: albert.berghuis{at}mcgill.ca

{triangledown} Published ahead of print on 11 May 2009.

{dagger} Supplemental material for this article may be found at http://aac.asm.org/.

Antimicrobial Agents and Chemotherapy, July 2009, p. 3049-3055, Vol. 53, No. 7
0066-4804/09/$08.00+0     doi:10.1128/AAC.00062-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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