Based on the β-lactam ring-opening mechanism, β-lactamases can be subdivided into two major groups. Serine β-lactamases (SBLs) use an active-site serine residue to covalently attack the β-lactam ring resulting in an inactive ring-opened product. Fortunately, several SBL inhibitors (such as clavulanic acid, sulbactam, tazobactam and avibactam) are clinically available as codrugs that are coadministered with β-lactam antibiotics to overcome SBL-related resistance. Metallo-β-lactamases (MBLs), typified by recently emerged New Delhi metallo-β-lactamase-1 (NDM-1), employ an active-site zinc-stabilized OH anion that acts as a nucleophile in β-lactam ring opening. MBL-producing pathogens are resistant to virtually all clinically used β-lactam antibiotics, including the last-resort antibiotics carbapenems. In fact, the first NDM-1-producing pathogen has been found in a diabetic patient. Despite the rapid spread of MBL-producing bacteria, which is a major threat to public health, no inhibitors of NDM-1 or other MBLs are clinically approved so far. Thus, there is a great need to develop selective MBL inhibitors as clinically relevant codrugs to restore the activity of β-lactam antibiotics.
The fungal natural product aspergillomarasmine A (AMA) has recently been identified as a selective and potent NDM-1 inhibitor and a promising codrug candidate both in vitro and in vivo (King et al., 2014, Nature 510:503-506). We have recently developed a simple biocatalytic method to prepare AMA and related aminopolycarboxylic acids (Poelarends et al., manuscript under review in Nature Catalysis). In this project, we will synthesize various aminopolycarboxylic acids, including novel analogues of AMA, as well as smart pro-drug versions of these compounds, and explore their bioactivity, target selectivity and therapeutic potential. As such, the proposed project will contribute to the development of new chemotherapeutic strategies to fight antibiotic-resistant pathogens, which are more prevalent in individuals with diabetes.