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Scientists have developed a deep learning model that could significantly accelerate the discovery of novel antibiotic compounds. In a study published today in Science Translational Medicine, the AI algorithm was able to identify two compounds effective against gonorrhea infections, each operating through mechanisms unlike those of any antibiotics in use today. 

“Faced with the threat of untreatable gonorrhea, new antibiotics are urgently needed,” writes James J. Collins, PhD, professor of medical engineering and science at the Broad Institute of MIT and Harvard. “Our work establishes a much-needed hit discovery tool to address the growing crisis of antimicrobial resistance for this pathogen.”

According to the CDC and WHO, gonorrhea is one of the most urgent antibiotic-resistant threats worldwide. When left untreated, this sexually transmitted infection can lead to serious health complications. Yet treatment is becoming increasingly challenging as strains of Neisseria gonorrhoeae continue to develop resistance to existing antibiotics. 

“Previous first-line therapies for gonorrhea—including penicillin, tetracycline, ciprofloxacin, cefixime, and azithromycin among others—are no longer recommended because of excessively high resistance rates in circulating strains,” says Collins. “The last remaining first-line monotherapy, ceftriaxone, is at risk of becoming obsolete, with resistance rates of over 10% in parts of the world.”

Traditional antibiotic discovery relies on high-throughput screening methods that search large chemical libraries for promising compounds. However, this approach cannot keep pace with the fast expansion of chemical space, which today englobes over 75 billion compounds. 

To overcome this limitation, Collins and colleagues turned to deep learning algorithms capable of making large-scale screening significantly more time- and cost-efficient. They selected a predictive graph neural network (GNN), a model that represents molecules as graphs and can virtually screen thousands of molecules per second. Compared to large language models, the GNN more accurately identified molecules with activity against gonorrhea that were structurally different from both the training data and existing antibiotics. 

To train the model, the team screened 38,650 small molecules with diverse structures and identified those capable of inhibiting the growth of N. gonorrhoeae. The model was then able to virtually screen through nearly six million compounds, which led to identification of 83 antibiotic candidates with confirmed activity against N. gonorrhoeae. 

Among them, two compounds stood out for having distinct structures from existing antibiotics, known as MP20 and A1. In mice and an organ-on-a-chip model of vaginal gonorrhea infection, both molecules rapidly and selectively killed the bacteria without inducing drug resistance. 

Proteomics analyses revealed the mechanism of action of each antibiotic candidate. MP20 was found to disrupt the bacterial membrane and damage DNA, while A1 targeted an enzyme essential for the synthesis of the bacterial cell wall. 

“There is a critical need to fill the trickling antimicrobial development pipeline with promising antibiotic candidates, especially ones with distinct mechanisms of action,” says Collins. “We have shown that these compounds can retain potency against even the most highly resistant strains of N. gonorrhoeae, exhibit selective killing toward bacteria, and act through orthogonal mechanisms from those of existing first-line antibiotics.”

The post AI Discovers Two New Antibiotics for Drug-Resistant Gonorrhea appeared first on Inside Precision Medicine.

Researchers at the Medical University of Vienna have identified a new role played by epidermal growth factor receptor (EGFR) signaling in metastatic colorectal cancer (mCRC), finding that its activity in myeloid immune cells helps shape the tumor microenvironment and influences tumor growth. The study, published in Cell Death & Differentiation, indicates that EGFR signaling does not affect only cancer cells but contributes to how immune cells regulate anti-tumor responses.

“Our results show that EGFR in myeloid cells is a key regulator of the tumor-promoting immune landscape,” said senior author Maria Sibilia, PhD, a professor of tumor biology and director of the Center for Cancer Research at Medical University of Vienna.

Metastatic colorectal is a leading cause of cancer-related deaths worldwide. EGFR-blocking antibody treatments are already part of standard first-line therapy for patients with wild-type KRAS/BRAF tumors, but not all patients respond to this form of treatment, and even among those that do respond, resistance frequently develops. The new findings help clarify why EGFR expression in tumor cells alone does not fully predict therapeutic outcomes and suggest that immune-cell signaling is an important factor in treatment response.

While, EGFR has been broadly studied as a tumor cell receptor, earlier research has suggested that EGFR-positive myeloid cells are associated with worse prognosis in CRC and hepatocellular carcinoma. Studies in mice had also shown that deleting EGFR in myeloid cells reduced tumor burden, while deleting it in tumor epithelial cells had limited effect. However, the contribution of immune-cell EGFR signaling on the response to anti-EGFR therapy has not been broadly studied or understood.

To address this, the Sibilia lab used genetically engineered mouse models of colorectal cancer with single-cell RNA sequencing, proteomic profiling, and combined it with analysis of patient-derived datasets. The team focused on tumor-associated myeloid cells, including macrophage subsets known to shape immune suppression within the tumor microenvironment. To allow direct comparison of outcomes, EGFR was selectively deleted in either myeloid cells or tumor epithelial cells in preclinical models.

Single-cell analyses showed that loss of EGFR in myeloid cells reduced populations of tumor-promoting macrophages, including Spp1⁺ and C1qc⁺ subsets, and altered signaling pathways linked to inflammation and immune regulation. Reduced activity in TGFβ, IFNγ, and JAK/STAT pathways was associated with decreased expression of immune checkpoint molecules and changes in myeloid–T cell communication. CD8+ T cells in EGFR-deficient tumors showed lower expression of exhaustion markers such as Pdcd1 and Havcr2, suggesting a shift in T cell functional state.

A key finding was the identification of thrombospondin-1 (THBS1) as a myeloid-derived ligand regulated by EGFR signaling. Further analysis confirmed that EGFR activity influences THBS1 expression in macrophages and patient data also showed that high expression of both EGFR and THBS1 correlated with poorer outcomes, and combined gene signatures were associated with reduced survival.

The researchers also noted that tumor-associated macrophages and other myeloid populations can shift between anti-tumor and tumor-promoting states, and that their role in EGFR-targeted therapy response had not been fully defined.

One conclusion drawn by the researchers based on their work is that myeloid EGFR signaling contributes to immunosuppression in mCRC and may affect treatment response to both targeted therapy and immunotherapy approaches. “These findings strongly suggest that targeting EGFR specifically in myeloid cells may be of great therapeutic benefit for patients with CRC,” the researchers wrote.

The data also indicate that therapeutic strategies that only address tumor cell EGFR likely don’t address the full landscape of its effects and may not indicate the extent of treatment response. Instead, the investigators suggested, modulation of EGFR signaling in immune cells, particularly macrophage populations, could improve the effectiveness of existing EGFR inhibitors and may enhance response to immune checkpoint blockade by reducing T cell exhaustion and checkpoint expression.

Building on this, the team will now investigate myeloid-specific EGFR inhibition strategies and explore targeted delivery methods, such as nanoparticles directed toward EGFR-positive macrophage populations. Additional work will also seek to validate THBS1 as a biomarker for patient stratification and to determine how targeting this pathway might be integrated with immunotherapy regimens.

The post Macrophage EGFR Activity Linked to Immune Suppression, Tumor Growth in Colorectal Cancer appeared first on Inside Precision Medicine.

CAR T therapy works best when it activates the tumor microenvironment in a specific way, according to a study published this week in Cell. When natural killer (NK) cells are activated, survival is extended. But if regulatory T cells and immunosuppressive myeloid cells are increased, that may blunt the therapy’s effects.

“We are now working to understand the exact mechanisms underlying response and resistance so we can continue to improve treatment,” Dana Silverbush, PhD, a co-author of the study and an assistant professor of Cancer Biology at University of Pennsylvania and Penn’s Perelman School of Medicine, told Inside Precision Medicine. Other co-authors were Perelman’s Zev Binder, MD, PhD, assistant professor of neurosurgery, and Cécile Alanio, MD, PhD, adjunct professor of neurosurgery.

About a year ago, Phase I clinical trials using this team’s dual-target CAR T-cell therapy improved survival in glioblastoma (GBM) tumor treatment. But the study found that the therapy was triggering tumor reduction and extending survival in some patients, but not all. Relapse remained common.

CAR T-cell therapy is a personalized immunotherapy that uses a patient’s own immune cells to treat their cancer. While successful against blood cancers, it has not yet made significant inroads against solid tumor cancers

In this latest study, a bivalent CAR T-cell therapy was delivered via intracerebroventricular (ICV) injection. This delivers the therapy directly to the cerebrospinal fluid (CSF) surrounding the patient’s brain. As a result, researchers can sample CSF around the infusion at different times and then analyze the levels of immune activation.

“ICV results in greater numbers of CAR T cells reaching the tumor and avoids the need to cross the blood-brain barrier. There are other potential benefits, such as reduced systemic circulation of CAR T cells, which may help reduce the risk of on-target/off-tumor toxicity, that make ICV administration attractive,” Silverbush said. 

GBM is a dire diagnosis. It is the most common brain cancer in adults. There are no drugs approved for recurrent disease. Overall survival for newly diagnosed GBM is around 18 months.

These researchers found that while all patients’ immune systems were activated, there were key differences between those who responded to the treatment and those who did not. Patients who responded had strong activation of NK cells, linked to tumor shrinkage and longer survival. Specifically, those favorable outcomes correlated with expansion of CD56^dimCD16^pos cytotoxic NK cells.  

Non‑responders showed increased regulatory T cells and immunosuppressive myeloid cells, which appear to blunt the therapy.

These findings point CAR T-cell therapy towards new approaches, for example, researchers can try priming patients’ immune systems with drugs that deplete regulatory cells, or try to armor the CAR T cells with proteins that shut down regulatory T cells.

“Now that we can see on a cellular level how CAR T-cell therapy significantly changes the composition of the patient’s immune system, we can begin to investigate ways to improve the therapy so that more patients might respond to the treatment and that response will last longer,” said Silverbush.

“A lot of what we know about CAR T-cell therapy comes from treating blood cancers, which behave very differently from solid tumors like glioblastoma,” said Alanio. “We can’t do frequent brain surgery on patients receiving CAR T-cell therapy to monitor the tumor’s immune environment, but the ICV gives a unique window into a patient’s cancer that wouldn’t be available if the treatment were delivered another way.”

“When we look ahead to making our dual-target CAR T-cell therapy even more effective, these findings point us in a few promising directions,” added Binde. 

The post CAR T Success Hinges on Microenvironment Response in GBM appeared first on Inside Precision Medicine.