In vitro and in vivo Inhibitory Activity of NADPH Against the AmpC BER Class C beta-Lactamase
- 주제(키워드) antimicrobial resistance , class C beta-lactamase , AmpC BER , NADPH , beta-lactamase inhibitors , mouse infection model
- 주제(기타) Immunology; Microbiology
- 설명문(일반) [Na, Jung-Hyun; Park, Soo-Bong; Jeong, Bo-Gyeong; Cha, Sun-Shin] Ewha Womans Univ, Dept Chem & Nanosci, Seoul, South Korea; [Lee, Tae Hee; Chung, Kyung Min] Chonbuk Natl Univ, Med Sch, Dept Microbiol & Immunol, Jeonju, South Korea; [Lee, Tae Hee; Chung, Kyung Min] Chonbuk Natl Univ, Med Sch, Inst Med Sci, Jeonju, South Korea; [Kim, Min-Kyu] Korea Atom Energy Res Inst, Biotechnol Res Div, Jeongeup, South Korea; [Kim, Min-Kyu] Univ Sci & Technol, Dept Radiat Biotechnol & Appl Radioisotope Sci, Daejeon, South Korea; [Na, Jung-Hyun] KBIO Hlth, Div Discovery & Optimizat, New Drug Dev Ctr, Cheongju, South Korea
- 등재 SCIE, SCOPUS
- 발행기관 FRONTIERS MEDIA SA
- 발행년도 2018
- URI http://www.dcollection.net/handler/ewha/000000156803
- 본문언어 영어
- Published As http://dx.doi.org/10.3389/fcimb.2018.00441
초록/요약
beta-Lactamase-mediated resistance to beta-lactam antibiotics has been significantly threatening the efficacy of these clinically important antibacterial drugs. Although some beta-lactamase inhibitors are prescribed in combination with beta-lactam antibiotics to overcome this resistance, the emergence of enzymes resistant to current inhibitors necessitates the development of novel beta-lactamase inhibitors. In this study, we evaluated the inhibitory effect of dinucleotides on an extended-spectrum class C beta-lactamase, AmpC BER. Of the dinucleotides tested, NADPH, a cellular metabolite, decreased the nitrocefin-hydrolyzing activity of the enzyme with a K-i value of 103 mu M in a non-covalent competitive manner. In addition, the dissociation constant (K-D) between AmpC BER and NADPH was measured to be 40 mu M. According to our in vitro susceptibility study based on growth curves, NADPH restored the antibacterial activity of ceftazidime against a ceftazidime-resistant Escherichia coli BER strain producing AmpC BER. Remarkably, a single dose of combinatory treatment with NADPH and ceftazidime conferred marked therapeutic efficacy (100% survival rate) in a mouse model infected by the E. coli BER strain although NADPH or ceftazidime alone failed to prevent the lethal bacterial infection. These results may offer the potential of the dinucleotide scaffold for the development of novel beta-lactamase inhibitors.
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