Structural highlights
Publication Abstract from PubMed
Modification of aminoglycosides by N-acetyltransferases (AACs) is one of the major mechanisms of resistance to these antibiotics in human bacterial pathogens. More than fifty enzymes belonging to the AAC(6') subfamily have been identified in Gram-negative and Gram-positive clinical isolates. Our understanding of the molecular function and evolutionary origin of these resistance enzymes remains incomplete. Here we report the structural and enzymatic characterization of AAC(6')-Ig and AAC(6')-Ih from Acinetobacter spp. The crystal structure of AAC(6')-Ig in complex with tobramycin revealed a large substrate-binding cleft remaining partially unoccupied by the substrate, which is in stark contrast with the previously characterized AAC(6')-Ib enzyme. Enzymatic analysis indicated that AAC(6')-Ig and -Ih possess a broad specificity against aminoglycosides but with significantly lower turnover rates as compared to other AAC(6') enzymes. Structure- and function-informed phylogenetic analysis of AAC(6') enzymes led to identification of at least three distinct subfamilies varying in oligomeric state, active site composition and drug recognition mode. Our data support the concept of AAC(6') functionality originating through convergent evolution from diverse Gcn5-related-N-acetyltransferase (GNAT) ancestral enzymes, with AAC(6')-Ig/Ih representing enzymes that may still retain ancestral non-resistance functions in the cell as provided by their particular active site properties.
Structural and biochemical characterization of Acinetobacter spp. aminoglycoside acetyltransferases highlights functional and evolutionary variation among antibiotic resistance enzymes.,Stogios PJ, Kuhn ML, Evdokimova E, Law M, Courvalin P, Savchenko A ACS Infect Dis. 2016 Oct 27. PMID:27785912[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Stogios PJ, Kuhn ML, Evdokimova E, Law M, Courvalin P, Savchenko A. Structural and biochemical characterization of Acinetobacter spp. aminoglycoside acetyltransferases highlights functional and evolutionary variation among antibiotic resistance enzymes. ACS Infect Dis. 2016 Oct 27. PMID:27785912 doi:https://dx.doi.org/10.1021/acsinfecdis.6b00058
