<p><strong>An international team led by researchers from CEITEC Masaryk University has developed a computational method for designing entirely new antimicrobial peptides – short proteins capable of killing bacteria. Instead of relying on the lengthy process of searching for suitable molecules in nature, the researchers can now use molecular simulations to predict their properties and design new molecules with specific functions. The resulting peptides successfully eliminated bacteria resistant to conventional antibiotics and proved effective in preclinical mouse models. The findings introduce a new approach to developing future antibiotics as well as other biologically active peptides.</strong></p><p>According to the World Health Organization, antibiotic resistance is one of the greatest global health threats of our time. Every year, the number of bacteria resistant to available antibiotics continues to grow. At the same time, developing new drugs is a lengthy and costly process in which most candidate molecules ultimately fail.</p><p>Researchers at <strong>CEITEC Masaryk University </strong>have therefore taken a different approach. Rather than searching randomly for antimicrobial compounds, they developed a method for designing them based on molecular design principles. Using molecular simulations, they analysed around <strong>150 peptides</strong> in detail and identified the rules that govern the design of molecules capable of forming stable pores in bacterial membranes. These tiny openings disrupt the membrane barrier, causing bacteria to lose control of their internal environment and ultimately die. <i>"We discovered how to arrange specific amino acids so that the resulting peptides form pores in bacterial membranes. This now allows us to generate an enormous number of peptide candidates and select those with the properties we are looking for,"</i> says <a target="_blank" rel="noopener noreferrer" href="https://www.ceitec.eu/prof-robert-vacha-ph-d/u27252"><strong>Robert Vácha</strong></a> from<strong> CEITEC Masaryk University</strong>, who led the research.</p><p>The researchers validated the most promising peptide designs experimentally. They confirmed their activity against a group of the most dangerous antibiotic-resistant bacteria. The best results were achieved against <strong>Acinetobacter baumannii</strong>, which the World Health Organization classifies as a priority drug-resistant pathogen. The team also demonstrated that their most successful peptide does not damage human red blood cells and shows no significant toxicity towards human cells. Its efficacy was further confirmed in two preclinical mouse models of bacterial infection.</p><p>The significance of the study lies not only in identifying a new antibiotic candidate but, more importantly, in establishing a new design strategy. Based on their findings, the researchers developed a set of design principles and 52 sequence templates that can be used to design approximately<strong> 10 trillion molecules</strong>, providing other research teams with a framework for developing new membrane-disrupting peptides. The same principle that proved successful against bacteria could also be applied in the future to develop anticancer therapeutics, biosensors, or targeted drug delivery systems.</p><p><i>"Until now, researchers have mostly searched for biologically active molecules created by nature and only then investigated how they work. We reversed this process. First, we studied which molecular properties are required for a particular mechanism of action – in our case, the ability to stabilize membrane pores – and then used this knowledge to design entirely new peptides that make such pores. This approach could significantly accelerate the development of new medicines and help us keep pace with the growing challenge of antibiotic resistance,"</i> adds Robert Vácha, who has received <strong>ERC grants</strong> for his research.</p><p>The study was carried out in collaboration with researchers from the <strong>University of Pennsylvania, the University of Groningen, Palacký University Olomouc, and the Institute of Microbiology of the Czech Academy of Sciences</strong>. The results were published in <a target="_blank" rel="noopener noreferrer" href="https://www.nature.com/articles/s41589-026-02269-z.epdf"><strong>Nature Chemical Biology</strong></a>.</p><blockquote><h4><strong>The original article</strong></h4><h4><a target="_blank" rel="noopener noreferrer" href="https://www.nature.com/articles/s41589-026-02269-z#citeas"><strong>Computational design of antimicrobial peptide nanopores</strong></a></h4><p>Rahul Deb, Marcelo D. T. Torres, Ivo Kabelka, Jan Přibyl, Kateřina Dvořáková Bendová, Edo Vreeker, Markéta Koběrská, Gabriela Balíková Novotná, Miloš Petřík, Giovanni Maglia, Cesar de la Fuente-Nunez &amp; Robert Vácha</p><p><i><strong>Nat. Chem. Biol.</strong></i>, 2026, <strong>22</strong>, 1–12</p><p><a target="_blank" rel="noopener noreferrer" href="https://doi.org/10.1038/s41589-026-02269-z"><span>https://doi.org/10.1038/s41589-026-02269-z</span></a><span>&nbsp;</span></p><h6>Licenced under <a target="_blank" rel="noopener noreferrer" href="https://creativecommons.org/licenses/by/4.0/"><strong>CC-BY 4.0</strong></a></h6></blockquote><h4><strong>Abstract</strong></h4><p>Antibiotic resistance is a global health threat, driving the need for new molecules that kill bacteria via nontraditional mechanisms. Here, we present a computational de novo design strategy for α-helical peptides that self-assemble into large, stable and membrane-spanning nanopores with antimicrobial activity, including in vivo efficacy against drug-resistant pathogens. Molecular dynamics simulations guided the selection of sequences for transmembrane barrel-stave pore formation, which were validated by microscopy, electrophysiology and fluorescence assays. Using computational and experimental analyses, including negative design controls, we developed general design guidelines and 52 modular sequence templates with tunable antimicrobial, pore-forming properties. Mechanistic studies confirmed bacterial cytoplasmic membrane disruption via designed nanopore formation. A tuned lead peptide selectively killed drug-resistant ESKAPEE bacteria, including <i>Acinetobacter baumannii</i>, without harming human cells, and showed anti-infective efficacy in preclinical mouse infection models. The framework presented here enables the design of synthetic peptide nanopores for precision antimicrobials, anticancer agents, molecular sensors and delivery systems.</p>

New Antibiotics Designed on a Computer: Scientists Develop a Blueprint for Building Molecules Against Drug-Resistant Bacteria 

<p><strong>A new study published in Nucleic Acids Research identifies short “start–stop” elements as highly effective regulators of protein synthesis in human cells. The study was co-led by Leoš Shivaya Valášek from IMIC CAS.</strong></p><section><div><p><img src="https://storage.googleapis.com/labrulez-bucket-strapi-h3hsga3/MBU_Nenapadne_start_stop_brany_reguluji_tvorbu_bilkovin_v_bunce_2_4d91bb348d.jpg" alt="MBU: Unassuming Start–Stop “Gates” Regulate Protein Production in Cells" srcset="https://storage.googleapis.com/labrulez-bucket-strapi-h3hsga3/thumbnail_MBU_Nenapadne_start_stop_brany_reguluji_tvorbu_bilkovin_v_bunce_2_4d91bb348d.jpg 245w," sizes="100vw" width="720" height="390"></p><section><div><p>An international team of scientists has described a&nbsp;previously overlooked mechanism that regulates the levels of important proteins in human cells. A new study published in <strong>Nucleic Acids Research </strong>reveals that short regulatory “start–stop“ elements act as highly effective speed-limiting gates of protein synthesis. Compared with previously known regulatory sequences, these elements were found to suppress protein production even more efficiently. At the same time, they help maintain low but stable levels of important proteins in cells, even under stress conditions. The study brought together scientists from the <strong>United States, the Czech Republic, Canada, and Sweden</strong>. <strong>Leoš Shivaya Valášek</strong>, Head of the <strong>Laboratory of Regulation of Gene Expression </strong>at the <strong>Institute of Microbiology of the Czech Academy of Sciences (IMIC CAS)</strong> was a&nbsp;co-author and one of the corresponding authors of the study.</p></div></section><section><div><p>During protein production, ribosomes read and translate information encoded in messenger RNA (mRNA) into amino acids, which are then assembled into a&nbsp;new protein. The researchers focused on an unusual sequence in which a&nbsp;start signal is immediately followed by a&nbsp;stop signal. As a&nbsp;result, the ribosome receives instructions to begin and terminate translation almost simultaneously. Although such an arrangement may appear illogical, it proved to be an important regulatory tool.</p><p><strong>Start–stop motifs </strong>are found in more than <strong>1,400 human genes</strong> and are particularly common in genes that control cellular signaling pathways, the stress response, or the activity of transcription factors—that is, proteins that regulate the activity of other genes. These genes must be tightly controlled because even small changes in the amount of their protein products can have significant biological consequences.</p><h4><strong>Resilience Under Stress</strong></h4><p>The researchers tested the activity of this regulatory mechanism under stress conditions, including in the ATF4 gene, which plays a&nbsp;key role in the so-called integrated stress response. Cellular stress is typically associated with a&nbsp;global reduction in protein synthesis. The authors demonstrated that regulation mediated by start-stop elements is largely independent of the overall state of translation initiation and therefore remains effective even under cellular stress.</p><h4><strong>A Stronger Brake Than Known Regulatory Elements</strong></h4><p>The team compared start–stop sequences with similar regulatory regions known as uTranslons. Although both types of elements suppress protein synthesis, the start–stop sequences proved to be significantly more effective. Ribosomes remain associated with these motives for longer before proceeding to the main coding region of the gene.</p><p><i>“Start-stop sequences are specialized regulatory elements that ensure increased ribosome retention, thereby allowing for fine-tuning translation,” </i>says Leoš Valášek from IMIC CAS.</p><p>The study expands our understanding of how cells fine-tune protein synthesis and may ultimately contribute to research on &nbsp;certain cancer and neurodegenerative disorders, and other diseases linked to disrupted protein production.</p></div></section><blockquote><h4><strong>The original article</strong></h4><h4><a target="_blank" rel="noopener noreferrer" href="https://academic.oup.com/nar/article/54/13/gkag627/8725953?login=false"><strong>Elongationless start–stop elements are stress-resilient translation gates that are more repressive than uTranslons</strong></a></h4><p>Justin Rendleman, Solomon A Haizel, Shaohuan Wu, Laurelle Lee Young, Junjie Liu, Xinyi Ge, Huijing Zou, Mahabub Pasha Mohammad, Matthew Pressler, Shuvadeep Maity, Vladislava Hronová, Zhaofeng Gao, Anna Hermannová, Anna Smirnova, Amy Lei, Kristina Allgoewer, Daniel Sultanov, Will Edward Hinckley, Ziyue Cheng, Lauren Shelby, Tanubrata Dey, Krzysztof J Szkop, Ivan Topisirovic, Ola Larsson, Maria Hatzoglou, Leoš Shivaya Valášek, Christine Vogel</p><p><i><strong>Nucleic Acids Research</strong> </i>(2026), Volume 54, Issue 13&nbsp;</p><p><a target="_blank" rel="noopener noreferrer" href="https://doi.org/10.1093/nar/gkag627">https://doi.org/10.1093/nar/gkag627</a></p><h6>licenced under <a target="_blank" rel="noopener noreferrer" href="https://creativecommons.org/licenses/by/4.0/"><strong>CC-BY 4.0</strong></a></h6></blockquote><h4><strong>Abstract</strong></h4><p>Start–stop elements are translation regulatory elements in 5′ untranslated regions (UTR) of eukaryotic transcripts, consisting of a start codon immediately followed by a stop codon. In contrast to canonical upstream Translons (uTranslons), they exclude elongation which creates unique properties. We conducted a comprehensive, carefully controlled comparison of human start–stop elements and uTranslons both at a genome-wide level and with targeted reporter assays. We found that start–stops and uTranslons were similar with respect to their presence in the 5′ UTRs of hundreds of genes, in particular transcription factors and signaling molecules, the low transcript levels of the corresponding genes, short RNA half-lives, and the negative effect on downstream translation. However, start–stop containing genes were translationally even more repressed than genes with uTranslons. Analysing the start–stop architecture and diverse ribosome footprinting datasets, we found evidence for a start–stop-specific mechanism that involves repeat cycling between initiation, termination, ribosome splitting, and 60S rejoining—a process possibly modulated by ASCC3 and eIF1. This cycling explained increased ribosome retention at start–stops and was—in contrast to ribosome retention at uTranslons—independent of the global initiation state. Finally, we showed that the start–stop element in human <i>ATF4</i> augments the core regulatory model by controlling translation of the uTranslons.</p></div></section>

Unassuming Start–Stop “Gates” Regulate Protein Production in Cells

Why Biologics QC Is So Much Harder Than Small Molecule Pharma

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Why Biologics QC Is So Much Harder Than Small Molecule Pharma

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