The antibiotic resistance problem: Two recent independent studies of the potential economic and social impact have concluded that 300 million people will die prematurely as a result of antimicrobial drug resistance over the next 35 years and that the world can expect to lose between 60 and 100 trillion USD worth of economic output by 2050 if the spread of antimicrobial drug resistance is not brought under control. Resistance to ?-lactam antibiotics: ?-Lactams remain the single most important antibiotic class. It is estimated that > 50% of all antibiotic prescriptions world-wide are for ?-lactam antibiotics (e.g. penicillins, cephalosporins, carbapenems). Carbapenems, the newest and most potent ?-lactams, have grown in importance as a first line treatment for the wide range of healthcare-associated infections caused by resistant Gram-negative bacteria. As few alternative treatment options are available, the increase in carbapenem- resistant isolates is a major global public health concern. In these organisms, the major resistance mechanism is production of enzymes called ?-lactamases that are able to degrade carbapenems (carbapenemases) in addition to other ?-lactams. There two categories of carbapenemases: the metallo ?-lactamases (MBLs) that rely on zinc ions for activity and the nucleophilic serine ?-lactamases (SBLs). Co-administration of ?-lactams and ?-lactamase inhibitors is a proven treatment strategy for ?-lactamase producers. Unfortunately, the clinically available ?-lactamase inhibitors are not very effective against newer SBL-type carbapenemases and are totally ineffective against MBLs. The recent FDA approval of avibactam that has good activity against many SBL-type carbapenemases is encouraging. However, avibactam is not active against MBLs and increasingly bacteria are found to produce both SBLs and MBLs. Project Aims: This proposal aims to identify and develop new ?-lactamase inhibitors that function by novel mechanisms that allow them to be inhibitors of both SBLs and MBLs and that may replace, or be combined with, existing agents in new generations of combination therapies effective against multiple classes of carbapenemase. The project is based on new mechanistic arguments concerning previously unrecognized potential chemical behavior of ?-lactams. It is hypothesized that strategic placement of certain groups adjacent to the ?-lactam C=O bond will create ?-lactams that fragment in a unique way when acted upon by either SBL- or MBL-type ?-lactamases to create products that are predicted to inhibit these enzymes. The project draws on the skills of three research groups whose expertise spans the areas of medicinal chemistry, biochemistry, structural biology and microbiology in a collaborative research effort to test this new approach to creating dual MBL/SBL inhibiting compounds that have the potential to alleviate the serious unmet medical need created by carbapenemase-producing resistant pathogenic bacteria.
The emergence of high-level resistance to ?-lactam antibiotics, the most important class of antibacterial agents, arises when bacteria produce enzymes called beta-lactamase enzymes that can destroy beta-lactams before they can exert their potent antibacterial activity. Inhibitors of specific ?-lactamases have been used effectively for the past three decades to combat this resistance phenomenon, but bacteria now produce new types of beta-lactamases called carbapenemases, against which the clinically available ?-lactamase inhibitors are no longer effective. We propose a totally new strategy for creating ?-lactamase inhibitors that promises to be effective in blocking this resistance mechanism leading to a restoration of the lifesaving properties of this very important class of antibacterial agents.