Novel rapid drug discovery for sepsis and agents for use as sepsis therapy

Description (excerpt)

GOVERNMENT INTEREST The invention described herein may be manufactured, used and licensed by or for the United States Government. BACKGROUND 1. Field of the Invention The invention relates to the general field of septic shock treatment, and in particular to a potential sepsis therapeutic drugs identified using a zebrafish screening model and use thereof. 2. Background The advances in care for the warfighter including body armor, medical/surgical care on and off the battlefield, and the rapid evacuation from the battlefield, have yielded a greater number of warfighters who survive injuries sustained on the battlefield, but unfortunately many of them succumb to complications from their wounds later. In particular, the high energy wounds sustained from gunshots, IEDs, and shrapnel that cause fractures are the most common in recent conflicts and are highly susceptible to bacterial infection including osteomyelitis (Yun et al. 2006; Petersen et al. 2007). These combat injuries account for approximately 65% of the total percentage of injuries and are evenly distributed between upper and lower extremities. In some cases, wound infections can lead to sepsis, which has a significant effect on increasing morbidity and mortality among military casualties. In Vietnam, sepsis was the third leading cause of death among those admitted to hospitals, and in Operation Iraqi Freedom and Operation Enduring Freedom, sepsis was found to be the fourth leading cause of potential survivable injuries behind central nervous system injury, hemorrhage, and airway disorders (Kelly et al., 2008). In addition, sepsis-related mortality is increasing, in part due to antibiotic resistance and increased bacterial virulence. The emergence of multidrug resistant bacteria has become a global problem for current antibiotic therapies, thus becoming a difficult challenge for hospitals worldwide, and it is a threat to effective treatment of infections among combat-wounded Service Members. Combat wound infections can progress rapidly to life-threatening sepsis with a median time of three days from injury to the onset of sepsis (Weintrob et al., 2018). A total of 5,278 sepsis hospitalizations were recorded in the active component of the U.S. military from 2011 to 2020 (Snitchler et al., 2021). A recent review of the Department of Defense Trauma Registry from 2007 to 2020 found that patients with combat injury related wound infections who were diagnosed with sepsis had significantly higher mortality rates than non-septic patients (21.9% vs. 4.3%, p<0.001) (Carius et al., 2021). The incidence of infection and sepsis is expected to increase in future conflicts due to multi-domain operations that will result in prolonged field care conditions. Sepsis is caused by a dysregulated host response to infection involving a complex (and not entirely understood) pathophysiology that leads to life-threatening organ dysfunction (Schlapbach et al. 2020). Because the mortality rate of sepsis patients continues to be comparatively high relative to non-septic patients, there is an urgent need for improved sepsis therapeutics that specifically address systemic infection and sepsis remediation, which can include modulation of the host response. Small molecule drugs that mitigate against dysregulated host responses to bacterial infection may provide the required systemic approach needed to prevent or treat sepsis. The discovery and development of therapeutics that mitigate against host-directed mechanisms responsible for triggering sepsis, to be administered in combination with antibiotics, is a viable research and development path for improving options available for preventing morbidity and mortality associated with sepsis. One problem with identifying new drugs or drug combinations for wound infection and sepsis is the lack of a preclinical model that has better predictive capability than cell-based systems but with higher throughput and lower cost than mammalian models (Philip et al., 2017). Therefore, a rapid, efficient screening model for sepsis therapeutics will accelerate discovery of novel therapeutics leading to improved warfighter survival and more rapid return to duty. In particular, a drug screening model that bridges the gap between poorly predictive in vitro tests and expensive, time-consuming rodent tests will greatly enhance a new development of therapeutics for sepsis by allowing determination of drug bioactivity, toxicity and off-target side effects early in the drug discovery process (Bowman and Zon, 2010), thus filling a gap between in vitro or in silico testing and pre-clinical rodent testing. SUMMARY OF THE INVENTION A who