β-lactam-based antibiotics currently account for about 65% of all applied antibiotics, due to their broad-spectrum of activity and favorable safety profile, making this class of drugs the most common clinical approach for treating bacterial infections. Examples of these drugs, which contain a β-lactam ring in their structure, include naturally occurring penicillins, and synthetic cephalosporins, monobactams, and carbapenems. Antibiotics with a β-lactam core target bacterial transpeptidases—enzymes necessary for cell-wall synthesis—and they block the formation of cross-bridges between adjacent peptidoglycan chains, leading to bacterial death. Overuse of β-lactam antibiotics has led to an increase in microorganisms with multidrug resistance. In β-lactam antibiotics, this resistance is driven primarily by bacterial enzymes called b-lactamases. Researchers have now revealed the crystal structure, binding, and cleavage of moxalactam antibiotic bound to L1 metallo-β-lactamase (MBL) from the emerging pathogen Stenotrophomonas maltophilia using the U.S. Department of Energy’s Advanced Photon Source (APS). Drug discovery based on the details captured in this study could contribute key information to counteract antimicrobial resistance and provide tools in future pandemics. The results were published in the journal Nature Communications.
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Image: Fig. 1. TR-SSX crystal structure of moxalactam of the active site of L1 MBL, L1 active site structure at 150 ms with hydrolyzed moxalactam (in yellow-red-blue), zinc (magenta) and protein residues (in silver-blue-red).