Enzyme Inhibitors: The Best Strategy to Tackle Superbug NDM-1 and Its Variants

Multidrug bacterial resistance endangers clinically effective antimicrobial therapy and continues to cause major public health problems, which have been upgraded to unprecedented levels in recent years, worldwide. β-Lactam antibiotics have become an important weapon to fight against pathogen infections due to their broad spectrum. Unfortunately, the emergence of antibiotic resistance genes (ARGs) has severely astricted the application of β-lactam antibiotics. Of these, New Delhi metallo-β-lactamase-1 (NDM-1) represents the most disturbing development due to its substrate promiscuity, the appearance of variants, and transferability. Given the clinical correlation of β-lactam antibiotics and NDM-1-mediated resistance, the discovery, and development of combination drugs, including NDM-1 inhibitors, for NDM-1 bacterial infections, seems particularly attractive and urgent. This review summarizes the research related to the development and optimization of effective NDM-1 inhibitors. The detailed generalization of crystal structure, enzyme activity center and catalytic mechanism, variants and global distribution, mechanism of action of existing inhibitors, and the development of scaffolds provides a reference for finding potential clinically effective NDM-1 inhibitors against drug-resistant bacteria.