A Novel Negamycin Analogue for the Treatment of Multidrug-Resistant Gram-Negative Bacterial Infection
Abstract
Topic Area: Appili Therapeutics, Inc. (Appili) proposes to develop an antibiotic for the treatment of infections caused by multiple types of bacteria that are resistant to currently available drugs. This proposed project directly addresses the Antimicrobial Resistance FY18 PRMRP Topic Area and the development of novel and/or innovative interventions, diagnostics, and treatment for multidrug-resistant pathogens, especially those that can be used in austere settings Area of Encouragement. Central Critical Problem: There has been a significant global increase in the number of bacteria found to be resistant to currently prescribed antibiotics, especially in medical facilities. Thus, antimicrobial resistance is an urgent threat to public health, causing at least 700,000 deaths worldwide each year. The U.S. Centers for Disease Control and Prevention (CDC) has reported that each year >2 million Americans are infected with antimicrobial-resistant pathogens, resulting in 23,000 deaths and up to $20 billion in excess direct healthcare costs. Public health agencies around the world have highlighted antibiotic-resistant Gram-negative bacteria as pathogens of greatest concern as they are growing increasingly resistant to existing antibiotics and few novel antibiotics are in development to take their place. Costs of treating these infections, combined with unacceptably high mortality and negative patient outcomes, affirm the need for novel Gram-negative antibiotics. Despite the threat posed by these resistant bacteria, there are currently only a small number of new drugs in development. The strategies for development of new antibiotics usually focus on creating new generations of existing antibiotics, the problem with which is that once pathogens are already resistant against an antibiotic, resistance to a new generation antibiotic often develops quickly. This can also lead to a rise in resistance to existing antibiotics. Applicability and Impact of the Research: Negamycin represents a new structural class of ribosome-targeting antibiotics with a novel mode of action not susceptible to existing resistance mechanisms. Although negamycin is broadly active against multiple Gram-negative pathogens, it lacks efficacy to be a viable clinical candidate. In this proposed project, Appili seeks to build off the prior success of its experienced medicinal chemistry team, who have created modified negamycin molecules (analogues) that are more effective against pathogens with resistance to multiple existing antibiotics. Appili proposes to advance ATI-1503, a novel and potent negamycin analogue, as a candidate for treatment of complicated urinary tract infections (cUTI) and bladder infections caused by multiple drug-resistant (MDR) Enterobacteriaceae infections. ATI-1503 is a potent negamycin analogue and data to date supports its development as a preclinical candidate for treatment of MDR Enterobacteriaceae infections. Appili has assembled a team with the expertise needed to complete Investigational New Drug (IND)-enabling studies, and the specific aims proposed cover the work needed to complete existing and in-progress preclinical microbiology evaluation of ATI-1503 and the necessary manufacturing and IND-enabling studies necessary to initiate Phase I trials Thus, through completion of this project, Appili will be poised to initiate Phase 1 clinical trials with a broad-spectrum Gram-negative antibiotic effective against prominent and newly emerging antibiotic resistance. This project will lead to a novel class of negamycin-derived antibiotics and will represent a significant advance in our fight against MDR Gram-negative bacteria, for which the number of effective therapies is declining. Considering the predicted global rise in MDR pathogen incidence and the associated health consequences, the impact of developing and marketing a novel antibiotic may drastically improve patient outcomes.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910308
Entities
People
- Sridhar Narayan
Organizations
- Appili Therapeutics (Canada)
- United States Army