Biology subjects

Cummins, T.

Publications and source records attributed to Cummins, T..

4 recordsLinked to original sources

bioRxiv2026

Allosteric Inhibition of NDM-1 by Thanatin Preserves the Di-Zinc Center While Restricting Dynamics

The New Delhi metallo-{beta}-lactamase 1 (NDM-1) is a major driver of carbapenem resistance in Gram-negative pathogens, yet the molecular basis by which antimicrobial peptides inhibit this enzyme has remained unresolved. Thanatin, a disulfide-stabilized {beta}-hairpin peptide, was previously proposed to inactivate NDM-1 by displacing catalytic Zn{superscript 2} ions, but this model lacked direct structural support. Here, we combine high-resolution NMR spectroscopy, intermolecular NOE mapping, HADDOCK-guided docking, and molecular dynamics simulations to reveal a distinct zinc-retaining dynamic allosteric mechanism. Thanatin binds adjacent to the catalytic groove, preserving the native di-zinc coordination environment while simultaneously rigidifying the L3 catalytic loop, as confirmed by Zn-bound spectral fingerprints and EDTA titration experiments. This conformational restriction explains how the peptide inhibits the enzyme while maintaining a zinc-bound but catalytically compromised state, a finding that contrasts with zinc-displacement hypotheses and reconciles prior biochemical observations with structural data. In bacterial assays, this allosteric inhibition translates to a moderate restoration of carbapenem sensitivity, resulting in a 50% reduction in viable cell output even under high-level enzyme expression. Our findings establish a mechanistic framework for designing next-generation peptide inhibitors that target the dynamic vulnerabilities of metallo-{beta}-lactamases.

biophysics↗

bioRxiv2026

Discovery and characterization of small molecule inhibitors of CBL-B that act as intramolecular glue to enhance T-cell anti-tumor activity

CBL-B is a RING-type E3 ubiquitin ligase that acts as a critical negative regulator of T-cell activation. It promotes T-cell anergy and suppresses immune responses through ubiquitin-mediated control of signaling proteins at the immunological synapse. T cells deficient in CBL-B activity lose their dependence on CD28 co-stimulation, exhibit heightened activation and increased cytokine production, and fail to re-establish anergy. In addition, mice deficient in CBL-B activity reject tumors. Together, this cellular mechanism and in vivo phenotype suggest inhibition of CBL-B may be a viable immuno-oncology therapeutic strategy. Here, we report the rational design and execution of a high-throughput screen (HTS) to identify small molecule inhibitors of CBL-B. This campaign led to the discovery of a scaffold that inhibits CBL-B E3 ligase activity with micromolar potency. Structural characterization revealed an intramolecular glue mechanism, in which the compound stabilizes the closed state of CBL-B, preventing phosphorylation of a tyrosine residue that is critical for activation and E2 binding. Iterative structure-activity optimization yielded compounds with nanomolar activity that enhanced T-cell activation and cytokine secretion in primary human T cells and suppressed tumor growth in a syngeneic colorectal mouse model. Together, these studies validate the biological rationale for pharmacological CBL-B inhibition and enabled the de novo discovery of intramolecular CBL-B glue inhibitors. This work culminated in the identification of NX-1607, a first-in-class oral CBL-B inhibitor now in clinical development for cancer immunotherapy.

immunology↗

bioRxiv2024

Multi-conflict islands are a widespread trend within Serratia spp

Bacteria carry numerous anti-phage systems in defence islands or hotspots. Recent studies have delineated the content and boundaries of these islands in various species, revealing instances of islands that encode additional factors, including antibiotic resistance, stress genes, Type VI Secretion System (T6SS)-dependent effectors, and virulence factors. Our study identifies three defence islands in the Serratia genus with a mixed cargo of anti-phage systems, virulence factors and different types of anti-bacterial modules, revealing a widespread trend of co-accumulation that extends beyond T6SS-dependent effectors to colicins and contact-dependent inhibition systems. We report the identification of four distinct anti-phage system/subtypes, including a previously unreported Toll/IL-1 receptor (TIR)-domain-containing system with population-wide immunity, and two loci co-opting a predicted T6SS-related protein for phage defence. This study enhances our understanding of the protein domains that can be co-opted for phage defence and of the diverse combinations in which known anti-phage proteins can be assembled, resulting in a highly diversified anti-phage arsenal.

microbiology↗

bioRxiv2022

Age, experience, social goals, and engagement with research scientists may promote innovation in ecological restoration

Innovation in ecological restoration is necessary in order to achieve the ambitious targets established in United Nations conventions and other global restoration initiatives. Innovation is also crucial for navigating uncertainties in repairing and restoring ecosystems, and thus practitioners often develop innovations at project design and implementation stages. However, innovation in ecological restoration can be hindered by many factors (e.g., time and budget constraints, project complexity, and others). Theory and research on innovation has been formally applied in many fields, yet explicit study of innovation in ecological restoration remains nascent. In order to assess the use of innovation in restoration projects, including its drivers and inhibitors, we conducted a social survey of restoration practitioners in the United States. Specifically, we assessed relationships between project-based innovation and traits of: the individual practitioner (including, for example, age, gender, experience); company (including, for example, company size and companys inclusion of social goals); project (including, for example, complexity and uncertainty); and project outcomes (such as completing the project on time/on budget and personal satisfaction with the work). We found positive relationships between project-based innovation and practitioner traits (age, gender, experience, engagement with research scientists), one company trait (companys inclusion of social goals in their portfolio), and project traits (project complexity and length). In contrast, two practitioner traits, risk aversion and the use of industry-specific information, were negatively related to project-based innovation. Satisfaction with work outcomes was positively correlated with project-based innovation. Collectively, the results provide insights into the drivers and inhibitors of innovation in restoration and suggest opportunities for research and application.

ecology↗