An Indiana University researcher is pioneering an innovative approach to develop new antibiotics that could help address the growing problem of bacterial antimicrobial resistance, which is when bacteria and viruses no longer respond to antibiotic medicines.
Recent estimates indicate that each year there are 5 million infections globally associated with bacterial antimicrobial resistance, with 1.3 million resulting in deaths. The COVID-19 pandemic further strained healthcare systems and led to increased antimicrobial usage, exacerbating the rise in resistant infections. The absence of new antibiotics with novel mechanisms of action for nearly four decades has further worsened the situation, as bacteria swiftly develops resistance to analogs of existing drugs.
Dr. Steven Johnson, an associate professor of biochemistry and molecular biology at the IU School of Medicine, has developed a new class of antibiotics that could help treat difficult infectious diseases.
“Bacteria will always generate resistance, but finding a new biological pathway that current antibiotics do not target can prove to be more successful,” Johnson said.
Johnson’s research team, including collaborators across the U.S. and internationally, has been exploring the possibility of targeting bacterial GroEL chaperonin systems as a unique antibiotic strategy.
“GroEL is a molecular machine responsible for maintaining the functional integrity of many bacterial proteins; thus, by targeting this central node with inhibitors, a domino effect is triggered that disrupts a wide range of essential cellular processes and ultimately proves fatal to bacteria,” Johnson said. “Because no other drugs function by targeting GroEL, this strategy should be highly effective at killing bacteria that are resistant to current antibiotics.”
Dr. Johnson and his team have identified several classes of GroEL inhibitors and have been examining their antibiotic potential against six of the most prominent drug-resistant bacteria referred to as the ESKAPE pathogens. The acronym stands for Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species.
“We have been particularly focused on targeting drug resistant S. aureus bacteria as they are the most lethal, causing over 300,000 infections and around 11,000 deaths each year in the U.S. alone,” he said. “Nobody has identified GroEL inhibitors before, so we have developed lead inhibitors that rapidly kill bacteria with low toxicity to human cells and prohibit the bacteria from generating resistance, and the inhibitors are effective against actively-replicating bacteria and those that might be hiding out in biofilms. More recently, we have obtained results supporting that lead inhibitors are killing bacteria because they are targeting GroEL; that is, they are exhibiting on-target effects. Now, we are progressing into evaluating our inhibitors for safety and efficacy in animals.”
To help with translating his academic discoveries towards clinical development, Johnson has formed a biotech startup, BioEL, Inc., which is focusing on better understanding the ESKAPE pathogens. The IU School of Medicine, the Indiana Clinical Translational Science Institute and the NIH have helped establish the viability of the antibiotic strategy in Johnson’s academic lab. His lab is continuing to explore the basic science aspects of the research to gain a better understanding of the specific mechanisms of their inhibitors in cells. Johnson and his team are exploring whether their inhibitors can be more broadly effective against other pathogens, including Mycobacterium tuberculosis, Trypanosoma brucei parasites (the causative agents of African Sleeping Sickness), and other infectious organisms.
Johnson has disclosed several inventions to the IU Innovation and Commercialization Office, which has filed several patents to support his drug development efforts. Currently, he is seeking industry partners to translate his technologies towards clinical development.
Bri Heron, technology marketing manager at Indiana University’s Innovation and Commercialization Office, contributed to this story.
