Evolutionary trajectories of beta-lactamase CTX-M-1 cluster enzymes: predicting antibiotic resistance.

PLoS Pathogens
Angela NovaisJuan-Carlos Galán

Abstract

Extended-spectrum beta-lactamases (ESBL) constitute a key antibiotic-resistance mechanism affecting Gram-negative bacteria, and also an excellent model for studying evolution in real time. A shift in the epidemiology of ESBLs is being observed, which is characterized by the explosive diversification and increase in frequency of the CTX-M-type beta-lactamases in different settings. This provides a unique opportunity for studying a protein evolutionary radiation by the sequential acquisition of specific mutations enhancing protein efficiency and fitness concomitantly. The existence of driver antibiotic molecules favoring protein divergence has been investigated by combining evolutionary analyses and experimental site-specific mutagenesis. Phylogenetic reconstruction with all the CTX-M variants described so far provided a hypothetical evolutionary scenario showing at least three diversification events. CTX-M-3 was likely the enzyme at the origin of the diversification in the CTX-M-1 cluster, which was coincident with positive selection acting on several amino acid positions. Sixty-three CTX-M-3 derivatives containing all combinations of mutations under positively selected positions were constructed, and their phenotypic efficiency...Continue Reading

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Datasets Mentioned

BETA
AY005110
AJ310929
U95364
AJ005044
AF189721
AF174129
AF305837
AF252623
AF252622

Software Mentioned

PHYML
PAML
MESQUITE
Networks
MEGA
CLUSTALW
ModelTest
MrBayes

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