Identifying Oxacillinase-48 Carbapenemase Inhibitors Using DNA-Encoded Chemical Libraries

Bacterial resistance to beta-lactam antibiotics is largely mediated by beta-lactamases, which catalyze the hydrolysis of these drugs and continue to emerge in response to antibiotic use. beta-Lactamases that hydrolyze the last resort carbapenem class of beta-lactam antibiotics (carbapenemases) are a growing global health threat. Inhibitors have been developed to prevent beta-lactamase-mediated hydrolysis and restore the efficacy of these antibiotics. However, there are few inhibitors available for problematic carbapenemases such as oxacillinase-48 (OXA-48). A DNA-encoded chemical library approach was used to rapidly screen for compounds that bind and potentially inhibit OXA-48. Using this approach, a hit compound, CDD-97, was identified with submicromolar potency (K-i = 0.53 +/- 0.08 mu M) against OXA-48. X-ray crystallography showed that CDD-97 binds noncovalently in the active site of OXA-48. Synthesis and testing of derivatives of CDD-97 revealed structure-activity relationships and informed the design of a compound with a 2-fold increase in potency. CDD-97, however, synergizes poorly with beta-lactam antibiotics to inhibit the growth of bacteria expressing OXA-48 due to poor accumulation into E. coli. Despite the low in vivo activity, CDD-97 provides new insights into OXA-48 inhibition and demonstrates the potential of using DNA-encoded chemistry technology to rapidly identify beta-lactamase binders and to study beta-lactamase inhibition, leading to clinically useful inhibitors.