Uppala, J. | bioRxiv Science

bioRxiv2025

Quorum Sensing Regulators and Non-ribosomal Peptide Synthetases Govern Antibacterial Secretions in Xenorhabdus szentirmaii

The decades-long gap in antibiotic discovery has led to a significant health crisis due to antimicrobial resistance (AMR). The bacterial genus Xenorhabdus, which forms symbiotic relationships with the soil nematode Steinernema, are known to secrete a variety of antimicrobial compounds with potential effectiveness against AMR. These antimicrobial compounds are primarily bio-synthesized by non-ribosomal peptide synthetases (NRPS) and polyketide synthetase (PKS) genes. In this study, we report that X. szentirmaii produces high levels of antibiotic activity during the stationary phase against diverse bacteria including known antibiotic resistant pathogens. It possesses 17 operons to encode predicted NRPS and PKS enzymes, designated as ste1 through ste17. The ste15-ste16 and ste17 operons are predicted to produce the known antibiotics Pax peptide and Fabclavine, respectively. Additionally, the newly identified operons ste3, ste4, ste5, ste8, ste9, and ste14 consist of single genes, each containing two or more NRPS genes. The ste13 operon harbors two NRPS genes, while the ste7 and ste12 operons contain three NRPS genes each. Further, RNA-seq analysis showed that lsrF that encodes a quorum sensing autoinducer-2 (AI-2) aldolase was expressed at high levels during stationary phase. These findings provide evidence that X. szentirmaii uses quorum sensing (QS) to synchronize the expression of multiple NRPS and PKS enzymes responsible for synthesizing various antimicrobial compounds. This study underscores the potential to leverage these regulatory insights for maximizing commercial applications of novel antibiotics combating AMR, as well as broader industrial uses.

microbiology↗

bioRxiv2023

Adaptation to ER Stress by Slt2, Counterpart of Human MAP Kinase ERK1/2, via Enhancing Splicing and Translation of HAC1 mRNA in Saccharomyces cerevisiae

Unfolded protein response (UPR) is a cellular strategy to increase the protein folding capacity of cells in response to stress within the endoplasmic reticulum (ER). In metazoan cells, three major UPR sensors Ire1, PERK and ATF6 work in concert by simultaneously activating intracellular signaling pathways and modulating a series of physiological processes such as attenuation of the general protein synthesis and expression of protein chaperones. In yeast Saccharomyces cerevisiae, Ire1 is known to be the only UPR sensor, which mediates splicing of HAC1 mRNA in the cytoplasm and derepresses its translation. Hac1 is a transcription factor that increases the expression of protein folding enzymes and chaperones, thus enhancing the protein folding capacity of cells. In this study, we provide compelling evidence that kinase Slt2 plays a significant role in facilitating both the splicing and translation of HAC1 mRNA, while also serving as a key mediator in the activation of UPR genes through an alternative route. We also provide evidence that human extracellular signal-regulated kinase 1 (ERK1) or ERK2 served as a functional substitute for yeast Slt2 in the context of UPR. Furthermore, ERK1 exhibits an enhanced activation in human primary cells when grown in the presence of ER stressor. These findings collectively suggest that Slt2 responds to ER stress by activating the Ire1 pathway as well as initiating a parallel signaling pathway.

molecular biology↗