Department of Cellular Biology and Pharmacology, Florida International Universitygrid.65456.34, Herbert Wertheim College of Medicine, Miami, Florida, USA.
Purdue University Center for Cancer Research, Purdue University, West Lafayette, Indiana, USA.
Microbiol Spectr. 2021 Sep 3;9(1):e0050221. doi: 10.1128/Spectrum.00502-21. Epub 2021 Aug 11.
The soil bacterium Burkholderia gladioli GSRB05 produces the natural compound arsinothricin [2-amino-4-(hydroxymethylarsinoyl) butanoate] (AST), which has been demonstrated to be a broad-spectrum antibiotic. To identify the genes responsible for AST biosynthesis, a draft genome sequence of GSRB05 was constructed. Three genes, , in an arsenic resistance operon were found to be a biosynthetic gene cluster responsible for synthesis of AST and its precursor, hydroxyarsinothricin [2-amino-4-(dihydroxyarsinoyl) butanoate] (AST-OH). The gene product is a noncanonical radical -adenosylmethionine (SAM) enzyme that is predicted to transfer the 3-amino-3-carboxypropyl (ACP) group from SAM to the arsenic atom in inorganic arsenite, forming AST-OH, which is methylated by the gene product, a SAM methyltransferase, to produce AST. Finally, the gene product is an efflux permease that extrudes AST from the cells, a common final step in antibiotic-producing bacteria. Elucidation of the biosynthetic gene cluster for this novel arsenic-containing antibiotic adds an important new tool for continuation of the antibiotic era. Antimicrobial resistance is an emerging global public health crisis, calling for urgent development of novel potent antibiotics. We propose that arsinothricin and related arsenic-containing compounds may be the progenitors of a new class of antibiotics to extend our antibiotic era. Here, we report identification of the biosynthetic gene cluster for arsinothricin and demonstrate that only three genes, two of which are novel, are required for the biosynthesis and transport of arsinothricin, in contrast to the phosphonate counterpart, phosphinothricin, which requires over 20 genes. Our discoveries will provide insight for the development of more effective organoarsenical antibiotics and illustrate the previously unknown complexity of the arsenic biogeochemical cycle, as well as bring new perspective to environmental arsenic biochemistry.
土壤细菌格氏伯克霍尔德菌 GSRB05 产生天然化合物砷丁菌素 [2-氨基-4-(羟甲基砷酰基)丁酸盐] (AST)，已被证明具有广谱抗生素活性。为了鉴定负责 AST 生物合成的基因，构建了 GSRB05 的草图基因组序列。在一个砷抗性操纵子中发现了三个基因 、 和 ，它们是负责合成 AST 和其前体羟基砷丁菌素 [2-氨基-4-(二羟基砷酰基)丁酸盐] (AST-OH)的生物合成基因簇。 基因产物是一种非典型的自由基 -腺苷甲硫氨酸 (SAM) 酶，预计该酶将 SAM 的 3-氨基-3-羧基丙基 (ACP) 基团转移到无机亚砷酸盐中的砷原子上，形成 AST-OH，然后由 基因产物，即 SAM 甲基转移酶，将其甲基化生成 AST。最后， 基因产物是一种外排渗透酶，将 AST 从细胞中排出，这是产生抗生素的细菌的常见最后一步。阐明这种新型含砷抗生素的生物合成基因簇为继续抗生素时代增添了一个重要的新工具。抗生素耐药性是一个新兴的全球公共卫生危机，迫切需要开发新型强效抗生素。我们提出，砷丁菌素和相关的含砷化合物可能是一类新抗生素的前身，以延长我们的抗生素时代。在这里，我们报告了砷丁菌素生物合成基因簇的鉴定，并证明只有三个基因，其中两个是新的，需要用于砷丁菌素的生物合成和运输，而与磷丁菌素的磷酸酯对应物相反，需要超过 20 个基因。我们的发现将为开发更有效的有机砷抗生素提供深入了解，并说明砷生物地球化学循环的先前未知的复杂性，以及为环境砷生物化学带来新的视角。
