Two Steps Toward Resistance

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Science  31 Oct 2003:
Vol. 302, Issue 5646, pp. 747-749
DOI: 10.1126/science.302.5646.747d

Bacteria, notably Staphylococcus aureus, have fought back against the clinical use of β-lactam antibiotics, such as penicillin and methicillin, by acquiring resistance cassettes. These fall into two general categories: one that relies on an alternative transpeptidase (needed for bacterial cell wall synthesis) that is less sensitive to β-lactams and a second that activates synthesis of a β-lactam hydrolase. The latter pathway uses as its front-end sensor a membrane-bound receptor (BlaR in Bacillus licheniformis); binding of β-lactam to its extracellular domain triggers autoproteolysis of an intracellular loop, which leads eventually to inactivation of BlaI, the repressor of β-lactamase.

Kerff et al. provide the structure of the sensor domain of BlaR, and Van Melckebeke et al. provide the structure of the DNA binding domain of BlaI. Comparison of BlaR to the known structures of β-lactamases suggests that the former lacks an active site residue capable of acting as the general base in the deacylation step, explaining why it becomes stably modified by the β-lactam, a longevity that may be needed for communication with the cytoplasmic loop. BlaI belongs to the winged-helix family of DNAbinding proteins, and identification of the residues contacting the major groove enabled modeling of this complex as well as that of MecI, the structurally similar repressor of the transpeptidase. — GJC

Biochemistry 10.1021/bi034976a (2003); J. Mol. Biol. 333, 711 (2003).

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