인문학
사회과학
자연과학
공학
의약학
농수해양학
예술체육학
복합학
DBpia AI
AI 에이전트
AI 아이디어
AI 리더
AI 뷰어
Citeasy
크롬 서지관리 다운로드
지원사업
학술연구/단체지원/교육 등 연구자 활동을 지속하도록 DBpia가 지원하고 있어요.
커뮤니티
연구자들이 자신의 연구와 전문성을 널리 알리고, 새로운 협력의 기회를 만들 수 있는 네트워킹 공간이에요.
초록·키워드
Obafluorin is a <i>Pseudomonas fluorescens</i> antibacterial natural product that inhibits threonyl-tRNA synthetase (ThrRS). It acts as a broad-spectrum antibiotic against a range of clinically relevant pathogens and comprises a strained β-lactone ring decorated with catechol and 4-nitro-benzyl moieties. The catechol moiety is widespread in nature and its role in the coordination of ferric iron has been well-characterised in siderophores and Trojan horse antibiotics. Here we use a combination of mutasynthesis, bioassays, enzyme assays and metal binding studies to delineate the role of the catechol moiety in the bioactivity of obafluorin. We use <i>P. fluorescens</i> biosynthetic mutants to generate obafluorin analogues with modified catechol moieties. We demonstrate that an intact catechol is required for both antibacterial activity and inhibition of the ThrRS molecular target. Although recent work showed that the obafluorin catechol coordinates Zn<sup>2+</sup> in the ThrRS active site, we find that obafluorin is a weak Zn<sup>2+</sup> binder <i>in vitro</i>, contrasting with a strong, specific 1 : 1 interaction with Fe<sup>3+</sup>. We use bioassays with siderophore transporter mutants to probe the role of the obafluorin catechol in Fe<sup>3+</sup>-mediated uptake. Surprisingly, obafluorin does not behave as a Trojan horse antibiotic but instead exhibits increased antibacterial activity in the presence of Fe<sup>3+</sup>. We further demonstrate that Fe<sup>3+</sup> binding prevents the hydrolytic breakdown of the β-lactone ring, revealing a hitherto unreported function for the catechol moiety in natural product bioactivity.
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