Karl Ocius

Angew Chem Int Ed Engl. 2026 Mar 2;65(10):e23303. doi: 10.1002/anie.202523303. Epub 2026 Jan 28.

ABSTRACT

To address the ongoing Staphylococcus aureus drug resistance, we screened marine fungal extracts against a multidrug-resistant strain and performed a metabolome analysis to identified new antibiotics with larger molecular size. Targeted isolation yielded eight merocytochalasans, including four new compounds (1,4-6), structurally characterized by MS, NMR, and x-ray single-crystal diffraction data analysis. Compound 1 possessing a unique cage-like symmetrical skeleton, effectively suppressed growth, adhesion, and virulence of methicillin-resistant S. aureus (MRSA), demonstrated potent efficacy in reducing bacterial burden in a mouse skin infection model, and exhibited low resistance development potential. Mechanistically, 1 binds the transmembrane component of the ABC transporter TarGH, and inhibiting its ATPase activity.

PMID:41601438 | DOI:10.1002/anie.202523303

ACS Infect Dis. 2026 Feb 8. doi: 10.1021/acsinfecdis.5c00980. Online ahead of print.

ABSTRACT

The growing number of bacterial infections and the rise of antibiotic resistance require approaches for antimicrobial development. Peptidoglycan, essential for maintaining the integrity and shape of the bacterial cell wall, is regulated by the coordinated activity of peptidoglycan synthesis and remodeling enzymes. While peptidoglycan synthesis enzymes have served as antibiotic targets for decades, peptidoglycan hydrolases have remained largely underexplored. Here, we review recent advances in the development of small-molecule inhibitors of peptidoglycan hydrolases as antimicrobial targets.

PMID:41656975 | DOI:10.1021/acsinfecdis.5c00980

bioRxiv [Preprint]. 2026 Jan 15:2026.01.14.699546. doi: 10.64898/2026.01.14.699546.

ABSTRACT

Early-life enteric infection can have long-lasting effects on the microbiota-gut-brain (MGB) axis. Using a neonatal Enteropathogenic Escherichia coli (EPEC) model, we show that intestinal epithelial cell (IEC) NOD1 signaling coordinates mucosal immunity, barrier repair, and neuroimmune outcomes throughout early development and into adulthood. Neonates infected at postnatal day (P) 7 exhibited ileal inflammation, as demonstrated by increased expression of inflammatory cytokines (Il1β, Il6, Il12, Il22), chemokines/chemokine receptors (Ccl2, Cxcl1, Ccr2), and barrier-repair genes (Muc2, Slc26a3), with increased monocyte/macrophage infiltration and reduced epithelial proliferation in WT mice that was blunted in Nod1^ΔIEC mice. Neonatal infection of WT mice induced persistent defects into adulthood (P56), including increased intestinal permeability, sustained inflammatory/repair signatures, hippocampal inflammation, altered neurogenesis, and impaired recognition memory, which were largely absent in Nod1^ΔIEC mice, establishing a crucial role for IEC NOD1 as a determinant of long-term MGB remodeling. Microbially derived ligands of NOD2, muropeptides, isolated from probiotic Lactobacillus species attenuated EPEC-induced mucosal inflammation and chemokine induction without altering bacterial burden, demonstrating NOD2 host-directed immunomodulation. Together, these findings identify an important role for NOD-dependent signaling axis in the gastrointestinal tract that links early-life infection to enduring gut-brain dysfunction and reveals probiotic-derived muropeptides as candidate microbial therapeutics.

PMID:41648211 | PMC:PMC12871257 | DOI:10.64898/2026.01.14.699546

Transplant Cell Ther. 2026 Feb 2:S2666-6367(26)00065-5. doi: 10.1016/j.jtct.2026.01.031. Online ahead of print.

ABSTRACT

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) remains limited by inefficient donor cell engraftment, which is influenced by inflammatory stress responses triggered during conditioning and immune reconstitution. While immune-mediated barriers have been extensively studied, the molecular regulators within donor hematopoietic stem and progenitor cells (HSPCs) that influence engraftment efficiency remain less defined. NOD1 and NOD2 are cytosolic pattern recognition receptors (PRRs) traditionally known for sensing bacterial peptidoglycans and initiating innate immune signaling. However, emerging data suggest that NOD1/2 signaling may be directly activated by cellular stressors that intersect with cellular stress pathways critical to HSPC function. Our previous work has demonstrated that NOD1 and NOD2 play a critical role in modulating sterile inflammation, a key component of the transplant environment. This positions these PRRs as potential regulators of HSPC stress responses and survival during transplantation. Despite this, the cell-intrinsic role of NOD1 and NOD2 in donor HSPC engraftment has not been fully explored. Understanding how these innate immune sensors influence HSPC function in the absence of infection could reveal novel strategies to improve engraftment and long-term chimerism following HSCT.

OBJECTIVE: This study aims to determine whether the cytosolic pattern recognition receptors NOD1 and NOD2 intrinsically regulate hematopoietic stem cell reconstitution and to define the underlying mechanisms by which their deletion may enhance donor cell persistence and chimerism in transplant settings.

STUDY DESIGN: We evaluated NOD1/2 expression in murine HSPCs, tested reconstitution efficiency of wild-type (WT) versus NOD1/2 double knockout (NOD1×2^⁻/⁻) donor cells in syngeneic and allogeneic recipients, and performed competitive transplant assays to assess cell-intrinsic effects. In addition, we tested the effect of NOD1/2 deletion in HSPCs on long-term survival, allograft rejection and tumor immunosurveillance. Transcriptomic profiling was performed to define mechanisms underlying altered reconstitution.

RESULTS: HSPCs constitutively expressed NOD1 and NOD2, and their transcription was upregulated by endotoxin and NOD ligands. Genetic deletion of NOD1/2 significantly increased donor cell reconstitution and long-term chimerism in both syngeneic and fully allogeneic recipients, with NOD1×2^⁻/⁻ cells outcompeting WT cells in competitive transplantation. Enhanced chimerism was observed across bone marrow, blood, spleen, and lymph nodes, without altering immune lineage differentiation. NOD1×2^⁻/⁻ chimeras showed normal survival, intact alloresponsiveness, and preserved tumor immunosurveillance. Transcriptomic profiling revealed significant reprogramming of NOD1×2^⁻/⁻ donor HSPCs, with highly significant alterations in mitochondrial metabolism, inflammatory signaling, and oxidative stress responses in the NOD1×2^-/- HSPCs, suggesting metabolic reprogramming as a mechanism of improved chimerism.

CONCLUSIONS: NOD1 and NOD2 act as innate immune checkpoints that restrict donor HSPC reconstitution. Their simultaneous absence enhances chimerism without compromising immune defense or tolerance and reprograms stem cell metabolism to favor survival. Targeting NOD1/2 signaling may represent a novel strategy to improve hematopoietic stem cell transplantation outcomes.

PMID:41638572 | DOI:10.1016/j.jtct.2026.01.031