Enzyme structural plasticity and the emergence of broad-spectrum antibiotic resistance.
The emergence of multi-resistant pathogenic bacteria is a worldwide health issue. Recently, clinical variants of a single antibiotic-modifying acetyltransferase, AAC(6')-Ib-a variant of aminoglycoside 6'-N-acetyltransferase-have been identified that confer extended resistance to most aminoglycosides and, more surprisingly, to structurally unrelated fluoroquinolones. The corresponding gene is carried by mobile genetic elements and is present in most multi-resistant pathogenic strains, hence making it a serious threat to current therapies. Here, we report the crystal structures of both narrow- and broad-spectrum resistance variants of this enzyme, which reveal the structural basis for the emergence of extended resistance. The active site shows an important plasticity and has adapted to new substrates by a large-scale gaping process. We have also obtained co-crystals with both substrates, and with a simple transition state analogue, which provides new clues for the design of inhibitors of this resistance mechanism.
Maurice
Frédérique
F
Cristallographie and RMN Biologiques, Université Paris Descartes, CNRS, 4 Avenue de l'Observatoire, 75006 Paris, France.
Broutin
Isabelle
I
Podglajen
Isabelle
I
Benas
Philippe
P
Collatz
Ekkehard
E
Dardel
Frédéric
F
D000123:Acetyltransferases / Q000235:genetics* / Q000378:metabolism; D000583:Amikacin / Q000737:chemistry; D002939:Ciprofloxacin / Q000378:metabolism; D003460:Crystallization; D018432:Drug Resistance, Multiple / Q000235:genetics*; D005839:Gentamicins / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure
D005839:Gentamicins; D002939:Ciprofloxacin; D000583:Amikacin; D000123:Acetyltransferases; C056532:aminoglycoside N(6')-acetyltransferase