Appili's X-ray crystallography program has resolved multiple structures for our most promising compounds. These structures allow our chemistry team to visualize the drug binding its target, and generate new ideas and insights into how even more potent molecules can be generated.

With death rates from multi-drug resistant bacteria expected to surpass cancer by 2050, better options to combat this threat are one of the most urgent unmet patient needs in today’s medical landscape.

(1)

ATI-1503 is Appili’s negamycin program. It is a new class of broad-spectrum antibiotics targeting multi-drug resistant, Gram-negative bacteria, including the World Health Organization's (WHO) and the U.S. Centers for Disease Control and Prevention’s (CDC) top priority threats: Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and carbapenem-resistant Enterobacteriaceae (CRE).

 

According to the CDC, Gram-negative bacteria are among the greatest threats to human health. This urgent situation is due in large part to the lack of antibiotics with meaningful activity against Gram-negative bacteria. With broad-spectrum Gram-negative activity, negamycin is an ideal scaffold for novel antibiotic development.  In addition to addressing these serious pathogens, negamycin analogues have inherently favorable pharmacokinetic and toxicity profiles, and the potential to overcome resistance mechanisms that have caused currently available antibiotics to fail in many circumstances.

Appili’s ATI-1503 program builds on the work performed at AstraZeneca (AZ), prior to its exit from the antibiotic space. The former AZ project lead is now working with Appili to generate candidates in this program. Appili scientists have identified a way to address the issues that road-blocked the program in its earlier iterations, with new insights on how to improve potency and entry into target bacteria.

“Antimicrobial resistance within a wide range of infectious agents is a growing public health threat of broad concern to countries and multiple sectors. Increasingly, governments around the world are beginning to pay attention to a problem so serious that it threatens the achievements of modern medicine. A post-antibiotic era—in which common infections and minor injuries can kill—far from being an apocalyptic fantasy, is instead a very real possibility for the 21st Century.”

- WHO 2014 Global Antimicrobial Surveillance Report

This program has received funding and support from the U.S. Army’s Peer Reviewed Medical Research Program (PRMRP), Canada’s National Research Council (NRC), and the National Institutes of Allergy and Infectious Disease (NIAID), part of the National Institutes of Health.

 

As a unique program in anti-bacterial drug development targeting significant unmet patient needs, ATI-1503 provides significant opportunities for global partnering and collaboration with other pharmaceutical companies.

(1) O’Neill J (2014) Review on Antimicrobial Resistance