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Research Themes Drug discovery

A change to resistance

SBKB [doi:10.1038/sbkb.2011.47]
Featured Article - November 2011
Short description: Two structures of NDM-1 β-lactamase show how this enzyme can confer resistance to many antibiotics.

The active site of NDM-1, in which many of the residues responsible for substrate binding and catalysis are on flexible loops. Image courtesy of Jim Sacchettini.

The most widely used family of antibiotics, the β-lactams, have been a mainstay of clinical therapy since the discovery of penicillin in the early twentieth century. However, pathogenic bacteria have countered the widespread use of β-lactams through the continual adaptation of β-lactamase enzymes that catalyze their hydrolysis. In particular, the recently discovered New Delhi metallo-β-lactamase (NDM-1) enzyme has raised public health concern, as it confers resistance to all known β-lactam antibiotics, including the carbapenem class of β-lactams, which are generally considered the last line of defense. As part of the PSI MTBI partnership, Sacchetini (University of Texas Medical Branch), Joachimiak (PSI MCSG) and colleagues report two crystal structures of NDM-1 that explain this enzyme's broad substrate activity and may help in the future design of NDM-1 inhibitors.

The structures of NDM-1 show that its ability to hydrolyze many β-lactam substrates is due to its large and flexible active site. Compared to other metallo-β-lactamases, the active site of NDM-1 is 2 to 13 times larger in volume. This expanded size stems in part from the conformation of two active site loops, ASL1 and ASL4. In other metallo-β-lactamases these loops bridge over the active sites, whereas in NDM-1 they seem to be splayed outward, leading to a more open conformation of the active site and allowing greater access to potential substrates. Furthermore, amino acid substitutions in these loops, particularly in ASL1, allow them greater flexibility in correctly positioning a broad range of β-lactams for hydrolysis.

By capturing NDM-1 in both the apo and singly zinc-bound forms, the researchers have also shed insight into the catalytic mechanism of β-lactam inactivation. The structures suggest that NDM-1 can exist in three states, defined by whether the enzyme is bound to zero, one or two metals, and that hydrolysis of the β-lactam ring is facilitated by the activation of a zinc-bound water molecule. This mechanism is similar to that described for other metallo-β-lactamases, and may provide a basis for targeting other enzymes of the same family.

In conclusion, the structures of NDM-1 may contribute to the rational design of new drugs capable of treating bacteria that have acquired broad-spectrum antibiotic resistance.

Timothy Silverstein

References

  1. Y. Kim et al. Structure of apo- and monometalated forms of NDM-1—a highly potent carbapenem-hydrolyzing metallo-β-lactamase.
    PLoS ONE 6, e24621 (2011). doi:10.1371/journal.pone.0024621

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