Doris Mia Taylor; Justin Anglin; Suhyeorn Park; Melek N. Ucisik; John C. Faver; Nicholas Simmons; Zhuang Jin; Murugesan Palaniappan; Pranavanand Nyshadham; Feng Li; James Campbell; Liya Hu; Banumathi Sankaran; B. V. Venkataram Prasad; Hongbing Huang; Martin M. Matzuk; Timothy G. Palzkill
ACS Infect. Dis., 2020, 6(5), 1214-1227
https://doi.org/10.1021/acsinfecdis.0c00015

Abstract

Bacterial resistance to β-lactam antibiotics is largely mediated by β-lactamases, which catalyze the hydrolysis of these drugs and continue to emerge in response to antibiotic use. β-lactamases that hydrolyze the last resort carbapenem class of β-lactam antibiotics (carbapenemases) are a growing global health threat. Inhibitors have been developed to prevent β-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 sub-micromolar potency (Ki = 0.53 ± 0.08 µM) against OXA-48. X-ray crystallography showed that CDD-97 binds non-covalently 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 two-fold increase in potency. CDD-97, however, synergizes poorly with β-lactam antibiotics to inhibit the growth of bacteria expressing OXA-48 due to poor accumulation in 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 β-lactamase binders and study β-lactamase inhibition, leading to clinically useful inhibitors.