ABSTRACT
After more than 80 years of development, ß-lactam drugs have become the most widely used high-efficiency, low-toxic broad-spectrum antibacterial drugs. However, with the widespread use and even abuse of those drugs, the resistance of major pathogens to ß-lactam drugs has increased over years, which has become a thorny problem to the public health. A common mechanism of the resistance to ß-lactams is the producing of ß-lactamases, which can hydrolyze the ß-lactam ring and inactivate these drugs. Metallo-ß-lactamases (MBLs) are one kind of ß-lactamases that require metal ions for their catalytic activities. Although it is a well-known strategy to recover the efficacy of ß-lactams by the combination of ß-lactamase inhibitors, there are still no MBL inhibitors that can be used in clinical practice. Therefore, it is urgent to develop MBL inhibitors. This review outlines the currently discovered MBL inhibitors with an emphasis on various strategies and approaches taken to discover MBL inhibitors, which may lead to diverse classes of inhibitors. Recent progress, particularly new screening methods, and the rational design of potent MBL inhibitors are discussed.
Subject(s)
Anti-Bacterial Agents/chemistry , Models, Molecular , beta-Lactamase Inhibitors/chemistry , beta-Lactamases/chemistry , Anti-Bacterial Agents/history , History, 20th Century , History, 21st Century , Humans , Molecular Structure , beta-Lactamase Inhibitors/historyABSTRACT
ß-Lactams are the most widely used class of antibiotics. Since the discovery of benzylpenicillin in the 1920s, thousands of new penicillin derivatives and related ß-lactam classes of cephalosporins, cephamycins, monobactams, and carbapenems have been discovered. Each new class of ß-lactam has been developed either to increase the spectrum of activity to include additional bacterial species or to address specific resistance mechanisms that have arisen in the targeted bacterial population. Resistance to ß-lactams is primarily because of bacterially produced ß-lactamase enzymes that hydrolyze the ß-lactam ring, thereby inactivating the drug. The newest effort to circumvent resistance is the development of novel broad-spectrum ß-lactamase inhibitors that work against many problematic ß-lactamases, including cephalosporinases and serine-based carbapenemases, which severely limit therapeutic options. This work provides a comprehensive overview of ß-lactam antibiotics that are currently in use, as well as a look ahead to several new compounds that are in the development pipeline.
