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Identifying Oxacillinase-48 Carbapenemase Inhibitors Using DNA-Encoded Chemical Libraries
journal contribution
posted on 2020-03-25, 19:03 authored by 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 PalzkillBacterial 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 submicromolar potency
(Ki = 0.53 ± 0.08
μM) 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 β-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 β-lactamase binders and to study β-lactamase
inhibition, leading to clinically useful inhibitors.
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Keywords
compoundOXA -48. Synthesisβ- lactam antibioticsstudy β- lactamase inhibitionβ- lactamase bindersOXA -48 inhibitionDNA-encoded chemistry technologyOXA -48. X-ray crystallographyβ- lactamase-mediated hydrolysisOxacillinase -48 Carbapenemase InhibitorsDNA-encoded chemical library approachresort carbapenem classE . coliCDD -97DNA-Encoded Chemical Libraries
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