da Silva, F. A. | Search bioRxiv

bioRxiv2025

The peptide LyeTx I mnΔK induces transcriptomic reprogramming in a novel Multidrug-resistant Acinetobacter baumannii

Acinetobacter baumannii is a critical pathogen in healthcare-associated infections, and treatment is challenging due to the emergence of multidrug-resistant strains. Antimicrobial peptides, such as LyeTx I mn{Delta}K, a synthetic peptide derived of a toxin from the spider Lycosa erythrognatha, represent a promising alternative due to their broad-spectrum activity and synergistic potential with antibiotics like meropenem. This study aimed to compare the genomes of several A. baumannii strains, including a novel multidrug-resistant A. baumannii isolate (AC37), and to evaluate the antimicrobial effects of LyeTx I mn{Delta}K-alone and in combination with meropenem-through transcriptomic analysis. Genome assembly and annotation of AC37 revealed 31 antibiotic resistance genes, and phylogenetic analysis comprising 123 A. baumannii genomes, including the reference strain, identified three unique resistant genes in the AC37 strain. Mobilome analysis showed 13 genes associated with mobile genetic elements, including two of the unique genes, highlighting horizontal gene transfer events. Transcriptomic profiling revealed that treatment with LyeTx I mn{Delta}K peptide alone induced several differentially expressed genes, including two efflux pump operons. Additionally, pathways related to protein synthesis, export, and secretion were activated, indicating a broader cellular response to the peptide. The treatment with LyeTx I mn{Delta}K in combination with meropenem disrupted oxidative phosphorylation, further revealing the metabolic plasticity of the bacterial response to external stresses. This study characterizes a new A. baumannii isolate and provides new insights into the bacterial response to a potential novel therapeutic molecule.

bioinformatics↗

bioRxiv2024

Identification and characterization of alamandine-(1-5), a new component of the Renin-Angiotensin System with unique properties

The renin-angiotensin system (RAS) comprises a biochemical cascade that hydrolyzes angiotensinogen into several different bioactive peptides, which can activate different receptors promoting plenty of specific effects. The aim of this study was to evaluate the presence of the putative product of alamandine, the pentapeptide alamandine-(1-5) in the circulation and its biological activity. To accomplish this we have used mass spectrometry (MALDI/TOF/TOF, LC-MS/MS) and several methodologies including isolated blood vessels, isolated perfused hearts, isolated cardiomyocytes, blood pressure recording in freely-moving normotensive and hypertensive rats (SHR), high resolution echocardiography (VEVO 2100), central administration (ICV infusion and microinjection in the insular cortex), cell culture (endothelial cells and GPCR-transfected CHO cells) and wild type and Mas, MrgD or AT2R deficient mice. Our results show that alamandine-(1-5) circulates in the human and rodent blood and promotes many biological central and peripheral actions. More importantly, its plasma concentration is increased in pediatric nephropathic patients. A major role for plasma ACE activity in the formation of alamandine-(1-5) from alamandine was observed using plasma samples from Angiotensinogen-KO mice. Alamandine-(1-5) increased Baroreflex sensitivity and produced a long-lasting ([~]6 hours) anti-hypertensive effect in SHR, associated with a significant reduction in cardiac output. A particularly important effect of this pentapeptide was observed in isolated perfused heart and cardiomyocyte contractility (reduced inotropism). It was capable of stimulating NO production through all receptors from the renin-angiotensin protective arm, (MAS, MrgD and AT2R) in CHO-transfected cells. Our data shows that Alamandine-(1-5) exhibits selective actions that set it apart from traditional concepts of the vasodilatory axis of the RAS and that are possibly intricately linked to a complex interplay between Mas, MrgD and AT2 receptors. This novel finding suggests that RAS may possess a complexity that surpasses our current understanding.

physiology↗