Search for novel arsenic-containing antibiotics
Disciplines
Amino Acids, Peptides, and Proteins | Medical Biochemistry | Medical Cell Biology | Medical Toxicology | Public Health
Abstract (300 words maximum)
Arsenic (As), the “king of poisons”, surprisingly shows promise in medicine. With the increasing threat of antibiotic-resistant bacteria, there is an urgent need for new antibiotics. Notably, some bacteria utilize environmental As to produce unique antibiotics, as represented by arsinothricin (AST). AST effectively controls various pathogens while spare human cells, demonstrating the potential of As-containing antibiotics. Our objective is to build upon and delve into this unique connection and discover further As-containing antibiotics. To this end, we mined bacterial genome databases using the AST biosynthetic gene cluster (BGC), which led to discovery of novel BGCs in two Actynomyces strains Microbispora rosea and Amycolatopsis tolypomycina. Gene analyses suggest that these BGCs encode As-containing ribosomally synthesized and post-translationally modified peptides (RiPPs), which we named AsRiPP, where one gene encodes a precursor peptide with the remaining genes involved in post-translational modifications. From the M. rosea AsRiPP BGC, we selected four genes, which we hypothesize are the minimum required gene set to produce an As-containing precursor of the encoded AsRiPP. These genes were heterologously expressed in Escherichia coli in the presence of As and the AsRiPP production was analyzed, yet it has not been successful. In contrast, when A. tolypomycina was cultured with As, an organic arsenic species was produced. The organic As species, which was crudely purified from a large culture by anion exchange column chromatography, exhibited antibiotic activity, supporting our hypothesis that the strain produces an As-containing antibiotic, presumably the AsRiPP. Our results suggest further existence of As-containing antibiotics in nature, demonstrating the potential to broaden the spectrum of resources for antibiotic development. We will continue both approaches to verify the association of the AsRiPP BGCs and the discovered As organic species.
Academic department under which the project should be listed
CSM - Molecular and Cellular Biology
Primary Investigator (PI) Name
Masafumi Yoshinaga
Search for novel arsenic-containing antibiotics
Arsenic (As), the “king of poisons”, surprisingly shows promise in medicine. With the increasing threat of antibiotic-resistant bacteria, there is an urgent need for new antibiotics. Notably, some bacteria utilize environmental As to produce unique antibiotics, as represented by arsinothricin (AST). AST effectively controls various pathogens while spare human cells, demonstrating the potential of As-containing antibiotics. Our objective is to build upon and delve into this unique connection and discover further As-containing antibiotics. To this end, we mined bacterial genome databases using the AST biosynthetic gene cluster (BGC), which led to discovery of novel BGCs in two Actynomyces strains Microbispora rosea and Amycolatopsis tolypomycina. Gene analyses suggest that these BGCs encode As-containing ribosomally synthesized and post-translationally modified peptides (RiPPs), which we named AsRiPP, where one gene encodes a precursor peptide with the remaining genes involved in post-translational modifications. From the M. rosea AsRiPP BGC, we selected four genes, which we hypothesize are the minimum required gene set to produce an As-containing precursor of the encoded AsRiPP. These genes were heterologously expressed in Escherichia coli in the presence of As and the AsRiPP production was analyzed, yet it has not been successful. In contrast, when A. tolypomycina was cultured with As, an organic arsenic species was produced. The organic As species, which was crudely purified from a large culture by anion exchange column chromatography, exhibited antibiotic activity, supporting our hypothesis that the strain produces an As-containing antibiotic, presumably the AsRiPP. Our results suggest further existence of As-containing antibiotics in nature, demonstrating the potential to broaden the spectrum of resources for antibiotic development. We will continue both approaches to verify the association of the AsRiPP BGCs and the discovered As organic species.