Biology subjects

Mehi, O.

Publications and source records attributed to Mehi, O..

5 recordsLinked to original sources

bioRxiv2026

A global map of receptor-binding protein compatibility for the programmable design of Klebsiella and Acinetobacter phages

The narrow host range of bacteriophages limits their application against genetically diverse bacteria, motivating rational host-range modification. Progress in programmable engineering depends on establishing design principles that determine the compatibility of possible host-recognition modules with phage scaffolds. Here, we establish a genomics-guided framework that systematically identifies compatibility-determining adapter domains in receptor-binding proteins for the rational engineering of phages to target clinically relevant pathogen populations. Applying this approach to 1,270 phage genomes infecting Acinetobacter baumannii and Klebsiella pneumoniae, we show that viral diversity is highly structured: 60% of the 2,313 receptor-binding proteins group into only 19 major clusters sharing conserved N-terminal compatibility adapters. The structurally most conserved adapters in Autographivirales are associated with diverse capsule-degrading depolymerases. Known host-specificities within single-adapter clusters target capsule types that represent up to 29% of A. baumannii and 44% of K. pneumoniae carbapenem-resistant populations. Overall, we define a global repertoire of modular host-recognition components for programmable configuration of phage therapeutics.

microbiology↗

bioRxiv2026

Prevalent Gut Phages Encode Modular Adhesins Mediating Epithelial Binding and Endoplasmic Reticulum Trafficking

Bacteriophages are crucial components of the human microbiome and hold promise as therapeutic agents. Yet, their physical interactions with mammalian cells remain poorly understood. Here, we developed a high-throughput platform to identify phages that adhere to epithelial layers and the proteins that mediate this interaction. The identified phages encode immunoglobulin (Ig)-like domain-containing proteins that, when displayed on a non-adherent phage, confer epithelial binding and internalization in vitro, and increased phage retention in the mouse gut in vivo. Phages encoding these adhesins are among the most abundant and prevalent human gut phages, including crAss-like phages and a distinct cluster of uncharacterized myophages. Domain sequence variation alters epithelial interaction profiles, and internalized phages traffic to the endoplasmic reticulum through the Golgi apparatus, suggesting access to non-degradative internalization pathways. These findings reveal widespread phage-human interactions in the human virome, with potential impacts on health and implications for next-generation phage therapeutics.

microbiology↗

bioRxiv2024

Pathogen genomic surveillance as a scalable framework for precision phage therapy

Phage therapy is gaining increasing interest in the fight against critically resistant nosocomial pathogens. However, the narrow host range of bacteriophages hampers the development of broadly effective phage therapeutics and demands precision approaches. Here we combine large-scale phylogeographical analysis with high-throughput phage typing to guide the development of precision phage cocktails targeting carbapenem-resistant Acinetobacter baumannii, a top-priority pathogen. Our analysis reveals that a few strain types dominate infections in each world region, with their geographical distribution remaining stable within six years. As we demonstrate in Eastern Europe, this spatio-temporal distribution enables preemptive preparation of region-specific phage collections that target most local infections. Finally, we showcase the efficacy of a four-phage cocktail against the most prevalent strain type in both in vitro and in vivo animal infection models. Ultimately, genomic surveillance identifies patients benefiting from the same phages across geographical scales, thus providing a scalable framework for precision phage therapy. HighlightsO_LIA few carbapenem-resistant Acinetobacter baumannii types dominate infections worldwide C_LIO_LIPhylogeography reveals stable strain composition of individual countries over a six-year period C_LIO_LIThis spatio-temporal distribution allows preemptive preparation of region-specific phage collections C_LIO_LIA four-phage cocktail is efficacious against the most prevalent strain type in Europe. C_LI

microbiology↗

bioRxiv2024

Dominant suppressor genes of p53-induced apoptosis in Drosophila melanogaster

Apoptosis, the programmed cell death, is responsible for the removal of cells seriously damaged or unwanted in development. A major function of apoptosis is the removal of cells which suffered oncogenic mutations, thereby preventing cancerous transformation. By making use of the DEP transposon, a P element derivative made in our laboratory, we made an insertional mutagenesis screen in Drosophila melanogaster to identify genes which, when overexpressed, suppress the p53-activated apoptosis. The DEP element has Gal4-activatable, outward-directed UAS-promoters at both ends which can be deleted separately in vivo. In the DEP insertion mutants, we used the GMR-Gal4 driver to induce transcription from both UAS-promoters and tested the suppression effect on the apoptotic rough eye phenotype generated by an activated UAS-p53 transgene. By DEP insertions, seven genes were identified which suppressed the p53-induced apoptosis. In four mutants, the suppression effect was resulted by single genes activated by one UAS-promoter (Pka-R2, Rga, crol, Spt5). In the other three (Orct2, Polr2M, stg), deleting either UAS-promoter eliminated the suppression effect. In qPCR experiments we found that the genes in the vicinity of the DEP insertion also showed an elevated expression level. This suggested an additive effect of the nearby genes on suppressing apoptosis. In the eucaryotic genomes there are co-expressed gene clusters. Three of the DEP insertion mutants are included and two are in close vicinity of separate co-expressed gene clusters. This raises the possibility that the activity of some of the genes in these clusters may help the suppression of the apoptotic cell death.

genetics↗

bioRxiv2019

Chemical-genetic profiling reveals cross-resistance and collateral sensitivity between antimicrobial peptides

Antimicrobial peptides (AMPs) are key effectors of the innate immune system and promising therapeutic agents. Yet, knowledge on how to design AMPs with minimal cross-resistance to human host-defense peptides remains limited. Here, with a chemical-genetic approach, we systematically assessed the resistance determinants of Escherichia coli against 15 different AMPs. Although generalizations about AMP resistance are common in the literature, we found that AMPs with different physicochemical properties and cellular targets vary considerably in their resistance determinants. As a consequence, collateral sensitivity effects were common: numerous genes decreased susceptibility to one AMP while simultaneously sensitized to others. Finally, the chemical-genetic map predicted the cross-resistance spectrum of laboratory-evolved human-B-defensin-3 resistant lineages. Our work substantially broadens the scope of known resistance-modulating genes and explores the pleiotropic effects of AMP resistance. In the future, the chemicalgenetic map could inform efforts to minimize cross-resistance between therapeutic and human host AMPs.

microbiology↗