Jörg Vogel

The rise of antimicrobial resistance (AMR) among human pathogens is a serious threat to global health, demanding novel treatment strategies. Antibiotics based on programmable antisense oligomers (asobiotics) offer an attractive solution, as their specificity can be quickly updated to target resistant bacteria. To understand the genetic architecture of resistance to asobiotics, we used laboratory evolution assays to identify mutations that decrease susceptibility to antisense peptide nucleic acids (PNAs) in four major gram-negative pathogens: Escherichia coli , Klebsiella pneumoniae , Salmonella enterica , and Pseudomonas aeruginosa . Reduced susceptibility depended on the cell-penetrating peptide (CPP) conjugated to the PNA, with reduced uptake emerging as a common adaptation only against the (KFF) ₃ -K CPP. Accordingly, sbmA was consistently mutated across all species treated with (KFF) ₃ -K-conjugated PNAs. We further identified mutations related to translation, peptide transport, and the cell envelope, generating new hypotheses on the cellular response to CPP-PNA conjugates. By contrast, for (RXR) ₄ XB- acpP we observed only a modest resistance increase, driven by mutations in the PNA binding site that could be readily bypassed by changing the PNA sequence. These findings show that CPP identity strongly determines robustness against resistance evolution, and that laboratory evolution can illuminate the mechanisms of action of asobiotics.

Macrophages are essential for both, to clear pathogens and preserve tissue homeostasis, yet the molecular regulators of this equilibrium remain incompletely defined. Here, we identify SAILR (survival associated immune-regulatory RNA), a primate-specific long noncoding RNA (lncRNA), as a critical modulator of macrophage viability under infection conditions. SAILR is induced during monocyte-to-macrophage differentiation, but rapidly downregulated upon bacterial challenge in a nuclear factor kappa B (NF-κB) dependent manner. In both naïve and immune-activated macrophages, SAILR dampens the expression of adhesion, phagocytosis, and invasion factors, which include SIGLEC1 and MMP7. During infection with Salmonella Typhimurium, depletion of SAILR sensitizes macrophages to apoptosis, resulting in loss of intracellular replication niches and reduced bacterial recovery. Conversely, enforced SAILR expression promotes macrophage survival and increases intracellular pathogen burden. Mechanistically, SAILR interacts with the antiapoptotic adaptor protein 14-3-3β to support macrophage survival. Notably, downregulation of SAILR is mirrored in circulating immune cells from patients with severe COVID-19 and sepsis. Together, our findings position SAILR as a central regulator in linking macrophage survival to host–pathogen interaction and disease pathophysiology.

Bacteria encode diverse defence systems, including CRISPR–Cas, to recognize and cleave the DNA of bacteriophages (phages) and other mobile genetic elements¹. In response, phages encode anti-CRISPR (Acr) proteins that inhibit CRISPR–Cas activity by blocking DNA binding or cleavage². Here we report an unexpected mechanism by which the anti-CRISPR AcrVA2 inhibits Cas12a biogenesis. AcrVA2 binds conserved and functionally important amino acid residues near the Cas12a N-terminus and triggers selective degradation of cas12a mRNA as it is translated. Additionally, conserved residues in the AcrVA2 C-terminal domain enable co-sedimentation with ribosomes and polysomes, which is required to achieve targeted co-translational mRNA degradation. The AcrVA2 C-terminal domain is broadly conserved in homologs encoded by diverse mobile genetic elements, typically in hosts that lack cas12a, suggesting that these homologues may recognize and downregulate alternative substrates in other bacteria. These findings reveal a novel mechanism for molecular conflict and gene regulation in bacteria.

The Prevotellaceae family comprises abundant, taxonomically diverse bacteria of the human microbiota that exhibit remarkable intraspecies variability and distinct phenotypes during host-microbe interactions. Yet functional investigations are hampered by the limited genetic tractability of this medically important bacterial family, rendering it understudied. Here, we apply antisense oligomer (ASO) technology to selectively inhibit translation of single or multiple mRNAs across nine Prevotellaceae species. Using ftsZ - and mreB -related phenotypes as morphogenic readouts, we demonstrate that ASOs can function as a tunable system to study essential gene function. Further, we show that ASOs can selectively deplete target species from a synthetic Bacteroidales community. These results establish ASOs as practical tools for functional genomics and community modulation in otherwise genetically intractable anaerobic microbiota members.

RNAmed - Future Leaders in RNA-based Medicine is a unique graduate training program in the area of RNA-based medicine. Financed by the Free State of Bavaria, Germany, it is jointly run by several universities and research institutes from Würzburg, Regensburg and Munich. It aspires to equip doctoral students with a comprehensive idea of RNA therapeutics, spanning fundamental biology, translational research, clinical application, regulation, ethics, and societal implications. This integrative approach is meant to cultivate exceptional qualifications for careers across academia, industry, and policy. The RNAmed program held its 2025 annual retreat on San Servolo (Venice, Italy), with a total of 40 doctoral researchers, principal investigators (PIs), and invited guests from academia and pharmaceutical industry attending. The three-day program combined keynotes, student presentations, flash talks, a career panel and topic-table discussions of advances and challenges across RNA therapeutics to catalyze exchange and collaboration. Presentations highlighted emerging directions for antisense strategies, circular RNAs, delivery technologies, and AI-enabled molecular design, reflecting the program’s cross-disciplinary nature. Discussions emphasized shared priorities such as clear experimental standards, robust delivery solutions, and stronger academia–industry ties to accelerate safe, effective RNA medicines. Updates on RNAmed’s growth and extended funding underscored its mission to develop talent through integrated scientific and professional training. Overall, the retreat strengthened a network of early-career scientists and mentors committed to advancing RNA-based modalities from concept to clinic.

Neisseria meningitidis is a human-adapted commensal pathogen that must continuously balance nutrient acquisition with stress tolerance. Here, we identify a type II-C CRISPR/Cas-associated small RNA (scaRNA) as a posttranscriptional regulator of the efeUOB operon and oxidative stress responses. Using in vitro RNA binding and structure probing assays, we show that the scaRNA interacts with the 5′ untranslated region of efeO mRNA, leading to reduced translation of this component of the ferrous iron transporter EfeUOB. Consistent with this, efeO translational fusions demonstrate repression by the scaRNA, whereas a ΔscaRNA mutant shows increased reporter expression. We further show that meningococcal Cas9 (Nme1Cas9) is able to cleave scaRNA in vitro, but in vivo phenotypes are primarily scaRNA-dependent, indicating that Nme1Cas9 contributes, at most, indirectly to this regulation. In line with this observation, comparative proteomics revealed overlapping but distinct roles of scaRNA and Nme1Cas9 in oxidative stress adaptation, energy metabolism, and ion transport. While steady-state protein abundances did not capture all scaRNA-dependent effects, functional assays confirmed that scaRNA inactivation reduces survival under oxidative stress. Together, our results identify scaRNA-mediated repression of efeO as a novel posttranscriptional mechanism that contributes to stress adaptation in meningococci. These findings expand the functional repertoire of CRISPR-associated elements and suggest a role for small RNA-based regulation in iron-related stress adaptation in a major human pathogen.

Antimicrobial resistance poses a pressing global health challenge in the 21st century. The rapid increase and prevalence of multidrug-resistant bacteria will require novel approaches to develop new antibiotics. Major advances in nucleic acid-based therapeutics, particularly antisense technologies, could be one solution for developing precision antibiotics. The selectivity and specificity in the drug design of antibacterial antisense oligomers (ASOs) allows precise gene-specific silencing and ultimately enables targeting of currently undruggable gene products. Our goal here is to comprehensively review the advances in asobiotics (antisense oligomer biotics) leading to therapeutic success, including modifications in the nucleic acid backbone of ASOs, which have improved their properties and progresses in delivery. We will discuss utilization of ASOs against several pathogens, strategies to overcome resistance, and finally future scenarios and prospects for asobiotics as pathogen-specific therapy in the clinic.