Researchers use new methods to target potentially undiscovered beneficial therapeutic chemicals

mBio (2022). DOI: 10.1128 / mbio.03297-21 “width =” 800 “height =” 471 “/>

Phylogenetic composition of YQL / AZL protein in Streptomyces. (A) Azinomycin B reacts with the opposite strand of DNA to form an ICL that is not hooked by AlkZ. (B) Derived from chlormethine, E. Structure of nitrogen mustard ICL not hooked by coliYcaQ. (C) Phylogenetic tree of YcaQ-like (YQL, blue) and AlkZ-like (AZL, red / orange; AZL2, gray) Streptomyces protein (n = 897). The red and orange AZL clade distinguishes between HΦQ and QΦQ catalytic motifs. E.coliYcaQ and S.sahachiroiAlkZ proteins are labeled. (D) Sequence logos of catalytic motifs of YQL, AZL, and AZL2 proteins. Catalytic residues are marked with an asterisk. The color corresponds to the chemistry of the side chains. (E) Frequency of copies per Streptomyces genome as a percentage of all species analyzed (n = 436 species, 897 sequences). The significance (P) values ​​for one-way ANOVA with copy number polymorphisms are 0.0078 (YQL-AZL), 0.0033 (AZL-AZL2), and 0.3305 (YQL-AZL2), the latter not significant. (F) YQL / AZL match frequency. The blue shaded area represents the species that contains both subfamilies. The tan section represents species that contain either YQL or AZL. credit: mBio (2022). DOI: 10.1128 / mbio.03297-21

A team of researchers at the Eichman Lab is associated with the Evolutionary Studies Initiative and led a recently published project. mBio.. Graduate student Noah Bradley and undergraduate student Katie Wahl (BA21, BCB) were co-lead authors of research into compounds produced by bacteria.

Specifically, the group was interested in a series of chemicals known as natural products. Although these chemicals are produced by living organisms for specific purposes, they are often valuable because they can be used as antibiotics, anticancer drugs, or other treatments. As new drug-resistant strains evolve, it becomes increasingly important to find new weapons against resistant diseases.

In this study, researchers relied on a technique known as genome mining, which Bradley describes as a useful tool to identify. Gene cluster And the natural products they produce. Historically, genomic mining has targeted specific mechanisms used to produce natural products. However, some mechanisms can produce similar natural products. Therefore, the team’s approach is instead aimed at the process of providing bacteria with self-resistance to certain types of compounds.Specifically, they were interested in mining the gene clusters they generate. Genotoxicity Natural products — those that can form chemical bonds with DNA.

This group paid special attention to the DNA repair enzymes of two bacteria known as DNA glycosylases.

One AlkZ is found in Streptomy cessahachiroi and the other YcaQ is found in Escherichiacoli. These enzymes (and closely related enzymes) can eliminate the DNA damage caused by genotoxin. However, the genomic environment and function of AlkZ and YcaQ are very different.

AlkZ-like (AZL) enzymes tend to be localized within biosynthetic gene clusters, and Bradley says, “AZL proteins appear to be tailored for self-tolerance to certain natural products.”

However, (YQL) enzymes like YcaQ have not been detected in the cluster, and according to Wahl, “YQL proteins may be the general caretaker for removing various DNA damages.” ..

The pair of co-lead authors are excited about the implications of moving forward in results.

“In the short term, we hope to be able to screen about 70 feature-free gene clusters identified in our study for the discovery of new or useful genotoxic natural product targets,” Bradley said. increase.

“In the long run, we hope that our self-resisting genome mining framework will be applied to targeted discoveries in the scientific community. Natural products Of therapeutic benefit. We also envision the discovery of new DNA repair mechanisms with this approach, “Wahl added.

This project was born out of creativity as researchers were expelled from the lab by the COVID-19 pandemic. Eichmann looked back on Bradley and Wall’s strong work ethic and positive attitude.

“It was fun to see Noah and Katie carry out a project specially designed to be done at home during the lab’s closure. All of us continue to be involved while isolated. Not only is this research useful, but this research is a whole new research path for the laboratory. “

This work was also a great example of the interdisciplinary research being done in Vanderbild.

“From the early days of the pandemic, the project has evolved into a fruitful collaboration with Jacob Steenwyk, a graduate student at the Rockas Lab who helped phylogeny and genomic mining analysis,” Bradley said.

Bradley went on to say, “The Mass Spectrometry Research Center (MSRC) here in Vanderbild has also helped with important experiments on this project.”

New drug candidates identified by bacteria

For more information:
Noah P. Bradley et al, Bacterial Genotoxin Resistance-Inducing Mining Defines a Family of DNA Glycosylases, mBio (2022). DOI: 10.1128 / mbio.03297-21

Journal information:

Quote: Researchers using a new method, potentially obtained on April 5, 2022 from https: // Targeting undiscovered beneficial therapeutic chemicals (April 5, 2022)

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Researchers use new methods to target potentially undiscovered beneficial therapeutic chemicals

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