Development of a Negamycin Analogue Targeting the Translational Machinery in Gram-Negative Drug-Resistant Pathogens for the Treatment of Infections
Abstract
Topic Area: Appili Therapeutics Inc. 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 addresses the “Antimicrobial Resistance” Fiscal Year 2016 Peer Reviewed Medical Research Program Topic Area. Central Problem and Rationale: Injuries that have occurred as a result of combat or trauma, both in a military and civilian setting, have a high risk of infection. The infection may occur either at the time of injury or during treatment at hospitals. There has been a significant global increase in the number of bacteria found to be resistant to currently used antibiotics, especially in medical facilities. Each year in the United States (US), over two million people are infected with antibiotic-resistant bacteria, resulting in increased length of hospital stay, higher severity of illness, complications such as amputations of the infected area, and increased mortality. Currently, per year, 23,000 deaths in the US and 25,000 deaths in the European Union with an estimate of over 700,000 deaths worldwide are attributed to drug-resistant bacterial infections, a number predicted to rise to over 10 million worldwide by 2050. The major threat comes from a group called the ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) pathogens, most of which are resistant to multiple drugs, with Klebsiella pneumoniae being the most commonly found ESKAPE pathogens in the intensive care unit. 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 modifying existing antibiotics. This is because once pathogens already gain resistance against an antibiotic, resistance to a new generation antibiotic often develops quickly. This can also lead to a rise in resistance to existing antibiotics. In this proposed project, Appili Therapeutics seeks to use its experienced medicinal chemistry team to create modified negamycin molecules (analogues) that are effective against pathogens with resistance to multiple existing antibiotics. We seek to develop a drug that can be used at therapeutically effective doses, while retaining negamycin’s attractive safe properties. Negamycin represents a new class of antibiotic that works in a way that is not susceptible to any existing mechanisms of antibiotic resistance. Negamycin already has a lot of the qualities required to make it an excellent treatment option against resistant bacteria, including low frequency of resistance. Therefore, negamycin analogues are an ideal starting point for development of a new antibiotic for treatment of infections caused by resistant pathogens. Ultimate Applicability and Impact of the Research: Through the successful achievement of the objective of this proposed project, Appili will identify an efficient analogue of negamycin to treat emerging resistant bacterial infections. This will have a tremendous impact since, as stated above, there is a significant rise in the incidence of these resistant bacteria. The potential of this analogue will be demonstrated through this project, making it ready for further testing required for future human clinical use. This analogue could be used to treat infections caused by resistant pathogens that may have otherwise led to major complications or even death. The use of body armor and the advances in medical treatment capabilities have contributed to an increase in the survival from battlefield injuries and have allowed a more successful treatment of sustained wounds. Still, bacterial infections in these wounds have remained a problem. Resistant bacteria are now frequently found in the battlefield wounds of patients admitted to military medical centers in the US. Infections caus
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710180
Entities
People
- Sridhar Narayan
Organizations
- Appili Therapeutics (Canada)
- United States Army