Inhibition of IP6K1 Suppresses Neutrophil-mediated Pulmonary Damage in Bacterial Pneumonia
A personalized therapeutic approach for treating gram positive and gram negative bacterial infections of the lung
Background
Antibacterial resistance (AMR) to both Gram-positive and Gram-negative bacterial species is a serious global, public-health concern, in both developing and non-developing countries, accounting for ~5M deaths in 2019 alone. Despite numerous preventative initiatives being undertaken over the past several decades AMR continues, fueled by the misuse or overuse of antibacterial agents in both healthcare and agricultural industries. AMR is of particular concern regarding the treatment of acute respiratory tract infections like pneumonia, which is a leading cause of hospitalization and has high treatment costs and poses a significant health systems burden.
A major issue contributing to AMR with acute respiratory infections is that most of these infections are treated empirically, with antibiotic treatment being updated due to the significant wait time, costs, and resources needed for running comprehensive diagnosis tests. Additionally, prolonged inflammatory responses due to the host’s natural immune responses can lead to lung-tissue damage and scarring that further increases susceptibility to secondary or future infections and AMR.
One method to combat AMR associated bacterial-lung infections is to enhance the host’s natural defense mechanisms, such that the invading bacteria are effectively targeted through innate cellular mechanisms that employ white blood cells. Enhancing such host-specific intrinsic defense mechanisms can both reduce the amount of antibiotic dose needed to get an adequate response that can reduce treatment duration, AMR, and negative side effects of the medication itself. However, such a “personalized medicine approach” requires understanding of the specific inflammatory mechanisms and enzymes involved in host-specific infection management. Fine-tuning of such intrinsic host-mechanisms is essential to get the right balance of positively enhancing bacterial clearance while avoiding negative aftereffects of the inflammation itself like lung-tissue damage and scarring.
Technology Overview
Boston Children’s Hospital researchers have experimental evidence from mouse-models to support that the inositol hexakisphosphate kinase 1 (1p6k1) gene plays a major role in governing the cellular activity of white blood cells (WBC) involved in intrinsic host-inflammatory responses within the lung. Particularly, the inventors have discovered that inhibiting the activity of the 1P6k1 gene, either intrinsically or using a pharmacological blocker called TNP N6, enhances the bacterial-killing ability of the host while reducing the negative inflammatory aftereffects that can often lead to lung damage due to harmful WBC or neutrophil accumulation in the lung. This is surprising, as initially it was shown that inhibiting 1P6K1 activity in WBC/neutrophils themselves can increase inflammatory activity and accumulation. However, the inventors found that Ip6k1 is a key enzyme that modulates platelets in the lung, in turn affecting WBC/neutrophil responses, by discovering and demonstrating that neutrophil accumulation in the lung is regulated uniquely by platelets and not neutrophils. Inhibiting IP6K1 in platelets thus alters platelet activity in such a way that it reduces neutrophil accumulation, but only in the lung. This targeted strategy can be used as a personalized therapeutic management of both Gram-positive and Gram-negative bacterial infections to prevent AMR.
Further Details:
- Antimicrobial Resistance Collaborators. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet. 2022 Feb 12;399(10325):629-655. doi: 10.1016/S0140-6736(21)02724-0
- https://www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-threats-report-508.pdf
- Chakraborty A. The inositol pyrophosphate pathway in health and diseases. Biol Rev Camb Philos Soc. 2018 May;93(2):1203-1227. doi: 10.1111/brv.12392.
- Chung, H., Merakou, C., Schaefers, M.M. et al. Rapid expansion and extinction of antibiotic resistance mutations during treatment of acute bacterial respiratory infections. Nat Commun 13, 1231 (2022). https://doi.org/10.1038/s41467-022-28188-w
Benefits
The current invention offers a one-of-a-kind non-surgical and personalized intervention to effectively prevent and treat AMR resulting from gram positive/negative bacterial-lung infections.
Applications
Practical application of this genetic target can not only enhance the ability of existing host responses and treatments but also limit the use of excessive doses of medications particularly antibiotics that can lead to development of microbial resistance.
- Method to reduce neutrophil or WBC accumulation in the lungs
- Method to administer 1P6k1 inhibitor to the host
- Method to enhance the ability to prevent or treat lung infection of the host via 1p6k1 inhibitor, particularly bacterial pneumonia with neutrophil accumulation or increased polyP levels that increase phagocytosis
Patents
- Issued US patent 11,357,780. Issued on June 14th 2022
IP Status
