Eric Brown, a scientist at the Michael G. DeGroote Institute for Infectious Disease Research (IIDR) at McMaster University in Hamilton, Ontario, has discovered a drug combination that has the potential to change medical practice for the treatment of drug-resistant infections.
The IIDR is a world-leading centre for infectious disease antimicrobial resistance (AMR). The institute is a multi-disciplinary team of investigators and trainees working to solve the crisis in antibiotics through the discovery of the underpinnings of AMR and applying this knowledge to find new treatments and to inform clinical practice. AMR is an increasingly dangerous global health crisis and a threat to the practice of medicine. It is the result of bacteria acquiring genes that protect them from antibiotics.
Currently, there are bacterial strains that are resistant to most and even all current drugs. The misuse and overuse of antibiotics are making the crisis worse and the pharmaceutical industry, which used to supply new antibiotics, has not discovered a new class of drug since the early 1980s – over 30 years ago.
To address the AMR crisis, innovation in antibiotic discovery and alternatives to antibiotics are crucial.
The IIDR is at the forefront of such efforts and members, including Eric Brown, have made numerous advances in this area over the past decade. Brown’s latest project, which was published in Nature Microbiology this past March, is another drug discovery breakthrough for the institute.
Brown’s new discovery is a drug combination that targets Gram-negative bacteria, the superbugs that are resistant to all known antibiotics which the World Health Organization (WHO) identified this past February as of “critical priority” for their threat to human health.
“We looked for compounds that would mess with these bacteria, and I think we’re nailing it,” said Brown, who is also a professor of biochemistry and biomedical science at McMaster University’s Michael G. DeGroote School of Medicine.
Gram-negative bacteria are increasingly resistant to all antibiotics including last resort drugs, such as colistin, and lead to pneumonia, wound or surgical site and bloodstream infections, as well as meningitis in healthcare settings.
The bacteria have an intrinsically impenetrable outer shell that is a barrier to many otherwise effective antibiotics, and this makes these infections deadly, particularly in hospital settings. Brown and his team developed a technology to detect perturbations on the outer surface of Gram-negative bacteria and then tested a collection of 1,440 off-patent drugs in search of one that might compromise that barrier in the superbugs.
Drug screening was done at the Centre for Microbial Chemical Biology (CMCB), IIDR’s core facility and one of the first academic labs of its kind in Canada. The CMCB’s High Throughput Screening Lab has a unique library of molecules and drug screening capabilities that were vital in helping Brown and his team find the drug that breaks down the bacteria.
“These pathogens are really hard nuts to crack, but we found a molecule that shreds that shell and allows antibiotics to enter and be effective,” said Brown. The scientists discovered that a previously known antiprotozoal drug, pentamidine, disrupts the cell surface of Gram-negative bacteria, even the most resistant.
Pentamidine, when used with other antibiotics, was found to be particularly effective against two of the three pathogens, which the WHO has identified as having the most critical priority for development of new antibiotics. Those were Acinetobacter baumannii and the Enterobacteriaceae.
The combo therapy also had some impact on the third most critical bacterial pathogen, Pseudomonas aeruginosa. The discovery was found to be effective in the lab and in mice, but more work is needed to offset potential side effects and ensure human safety.
Brown added that his lab is continuing to test more compounds as well. “One of the things we want to pursue further is why this is working so well. Pentamidine seems to enable a large number of antibiotics to now be effective against Gramnegative bacteria that weren’t before.”
“Also, the fact that Pentamidine is an existing drug means it has strong potential for a much quicker path to the clinic.”
Brown and other scientists at the IIDR are continuing to look for other drugs that will break down Gram-negative bacteria and others. Using state-of-the-art infrastructure in drug discovery and innovation in pathogen surveillance, the IIDR offers new hope in the pressing battle against drug-resistant germs that kill thousands of people annually and threaten the very foundation of modern medicine.