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

Autor:	Taylor DM; Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, United States., Anglin J; Center for Drug Discovery, Baylor College of Medicine, Houston, Texas 77030, United States.; Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas 77030, United States., Park S; Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston, Texas 77030, United States., Ucisik MN; Center for Drug Discovery, Baylor College of Medicine, Houston, Texas 77030, United States.; Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas 77030, United States., Faver JC; Center for Drug Discovery, Baylor College of Medicine, Houston, Texas 77030, United States.; Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas 77030, United States., Simmons N; Center for Drug Discovery, Baylor College of Medicine, Houston, Texas 77030, United States.; Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas 77030, United States., Jin Z; Center for Drug Discovery, Baylor College of Medicine, Houston, Texas 77030, United States.; Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas 77030, United States., Palaniappan M; Center for Drug Discovery, Baylor College of Medicine, Houston, Texas 77030, United States.; Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas 77030, United States., Nyshadham P; Center for Drug Discovery, Baylor College of Medicine, Houston, Texas 77030, United States.; Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas 77030, United States., Li F; Center for Drug Discovery, Baylor College of Medicine, Houston, Texas 77030, United States.; Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas 77030, United States.; Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston, Texas 77030, United States., Campbell J; Center for Drug Discovery, Baylor College of Medicine, Houston, Texas 77030, United States.; Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas 77030, United States., Hu L; Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, United States., Sankaran B; Berkeley Center for Structural Biology, Advanced Light Source, Lawrence Berkeley National Lab, Berkeley, California 94720, United States., Prasad BVV; Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, United States., Huang H; Center for Drug Discovery, Baylor College of Medicine, Houston, Texas 77030, United States.; Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas 77030, United States.; Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston, Texas 77030, United States., Matzuk MM; Center for Drug Discovery, Baylor College of Medicine, Houston, Texas 77030, United States.; Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas 77030, United States.; Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston, Texas 77030, United States., Palzkill T; Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, United States.; Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston, Texas 77030, United States.
Jazyk:	angličtina
Zdroj:	ACS infectious diseases [ACS Infect Dis] 2020 May 08; Vol. 6 (5), pp. 1214-1227. Date of Electronic Publication: 2020 Mar 25.
DOI:	10.1021/acsinfecdis.0c00015
Abstrakt:	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 submicromolar potency ( K i = 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.
Databáze:	MEDLINE
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