Research Roundup: May 14, 2021

SARS-CoV-2 genes, bacteria's paths to antibiotic resistance, IBD microbes' inflammatory features, and more

Broad Communications
Credit: Broad Communications

Welcome to the May 14, 2021 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.

Viral comparisons resolve the full SARS-CoV-2 gene set

Though the SARS-CoV-2 genome was first sequenced early in the pandemic, its gene content has remained unresolved until now. Irwin Jungreis, Rachel Sealfon (Flatiron Institute), and associate member Manolis Kellis of the Epigenomics Program used comparative genomics of 44 Sarbecovirus strains to confirm six accessory proteins, reject several candidate genes, and discover a new alternate-frame gene overlapping ORF3a. They also used their comparisons to prioritize functional mutations among 2,544 pandemic isolates, identify unusually rapidly- or slowly-evolving genes (compared to their evolutionary history), and flag mutations likely to underlie infectivity differences between variants. Learn more in Nature Communications and an MIT story.

The evolution of drug resistance

Antibiotic resistance is one of the most urgent threats to public health, yet researchers’ understanding of how pathogens evolve resistance remains limited. To address this gap, Peijun Ma, Infectious Disease and Microbiome Program (IDMP) co-director Deborah Hung, and colleagues investigated the evolution of carbapenem resistance in Klebsiella pneumoniae, a bacterial species that can cause deadly multi-drug-resistant infections. They identified multiple genetic factors that facilitate the rise of carbapenem resistance, and propose that defining infecting pathogens at a much higher genetic granularity (beyond simply species identity and antibiotic susceptibility) can have important implications for diagnosing and treating such infections. Read more in eLife.

Bacterial enzymes enable specific antimicrobial activity 

Prodrugs, compounds that are metabolized in the body to become active drugs, can be used as antimicrobial drugs if their activation relies on the activity of an enzyme found only in their microbial target. In ACS Chemical Biology, Kenton Hetrick, Miguel Aguilar Ramos (MIT), and Chemical Biology and Therapeutics Science Program associate member Ron Raines reported that a sulfurol ester prodrug of the antibiotic trans-3-(4-chlorobenzoyl)acrylic acid is more effective against Mycolycibacterium smegmatis because an endogenous esterase  sensitizes it to the prodrug. Future work could harness a range of bacterial enzymes in developing narrow-spectrum antibiotics to help address the ongoing public health threat of antimicrobial resistance.

Inflammatory inconsistencies in IBD-linked microbes 

Patients with inflammatory bowel disease (IBD) often have increased levels of the gut microbe Ruminococcus gnavus. Matthew Henke (Harvard Medical School), senior associate member Jon Clardy of the Infectious Disease and Microbiome Program (IDMP), and colleagues used patient isolates of R. gnavus to study the molecular mechanisms underlying the microbe’s role in inflammation. The team identified a gene cluster that, when present, guides production of a thick polysaccharide protective capsule completely covering the cell. They found that mice colonized with strains lacking this cluster had more gut inflammation compared to those harboring capsule-producing strains, suggesting that not all R. gnavus strains are inflammatory. Read more in PNAS.

Knock your Sox off

SOX2 is a transcription factor targeted by chromosomal amplifications in esophageal squamous cell carcinoma (ESCC). Zhong Wu, Jin Zhou, Xiaoyang Zhang, former Cancer Program associate member Adam Bass (now at Columbia University Irving Medical Center), and colleagues developed engineered murine organoids representing phenotypes spanning normal esophagus to Sox2-induced squamous cell carcinoma, and mapped Sox2 binding and the epigenetic and transcriptional landscape with evolution from normal to cancer. Oncogenic Sox2 reprograms the tumor cell epigenome and promotes dependence on the RNA editing enzyme ADAR1. The work points to vulnerabilities that could be targeted with new treatment approaches. Read more in Nature Genetics.


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