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Researchers at McMaster University in Hamilton, Ontario, have discovered a new antibiotic, manikomycin, that kills drug-resistant bacteria through a previously unrecognized mechanism. The findings were published June 3 in Nature. 

Gerry Wright, PhD, a professor of biochemistry and biomedical sciences at McMaster, led the research team. Wright's group worked with collaborators at the University of Illinois in Chicago and the University of Hamburg in Germany.

Manikomycin is a natural depsipeptide, the first known antibacterial agent to target the E-site in the large ribosomal subunit. Because it's unaffected by resistance mechanisms found in bacterial clinical strains, it offers a new chemical scaffold for antibiotic development. 

"This new compound has shown early effectiveness against priority pathogens, including Salmonella, E. coli, and Klebsiella," Wright told Medscape News Canada. " There are many antibiotics that bind to the other sites, like tetracyclines, for example, which binds to the A-site. As a result, resistance builds up within those sites. Over the history of medicine, we've put absolutely no selective pressure on this particular target, so bacteria have no existing resistance mechanism for manikomycin." 

A Unique Mechanism of Action

Because it binds in the E-site of the bacterial ribosome's large subunit, manikomycin prevents the entry of the 3′ end of the tRNA into the E-site, thus hindering the translocation step of protein synthesis in a sequence-context-specific manner. It was developed through an improved fractionation approach that enriches previously overlooked minor products. Fractionating natural product extracts from soil bacteria, the researchers found that Streptomyces rimosus (the source of the antibiotic oxytetracycline) produces a cyclic depsipeptide antibiotic. 

Manpreet Kaur, a postdoctoral fellow in Wright's lab and first author of the study, noted that finding a viable new drug candidate this way signals new opportunities for antibiotic discovery. "There is likely so much still to be discovered through fractionation. Revisiting the extracts of even well-studied bacteria like Streptomyces may lead to similar discoveries in the future," she said in a statement.

Manikomycin-A showed acceptable acute tolerability in mice at doses up to 220 mg kg^-1 per day. But no efficacy was observed in initial mouse infection models, prompting a comprehensive pharmacokinetic evaluation. In vitro pharmacokinetics indicated excellent stability in mouse and human plasma, but the results suggest that the peak plasma concentration is inadequate. Follow-up studies will focus on improving the compound's pharmacologic properties. 

Increasing Prevalence of Antibiotic Resistance

The development of a new antibiotic to fight drug-resistant bacteria is significant, given the rise in antibiotic resistance. A 2024 study by The Lancet and the Global Research on Antimicrobial Resistance project reported that antimicrobial resistance directly caused about 1.14 million deaths per year globally. 

"Anyone who practices clinical medicine is aware of this phenomenon because we see it encroaching on our patient care, and it can be very challenging," Isaac Bogoch, MD, an infectious disease specialist at Toronto General Hospital, told Medscape News Canada. "While this is an issue in Canada, it's a much more significant issue in other parts of the world. There are a growing number of infections but fewer and fewer treatment options available." Antimicrobial resistance can delay the initiation of an appropriate antibiotic, thus increasing morbidity and mortality. 

"This preclinical research is extremely important," continued Bogoch. "It's an exciting development because we need newer classes of antibiotics coming through the pipeline, and most drugs in development won't make it through phase 3 clinical trials and be marketable. If you have a diverse panel of drugs that can combat a growing threat of antimicrobial resistance, it's an extremely important way of dealing with the growing problem of antimicrobial resistance. However, the elephant in the room is that we need to use fewer antibiotics. We're using a very precious resource inappropriately." 

"Roughly 70% of antimicrobial consumption is in animal health, farming, agriculture, and aquaculture communities, and this is where a lot of antimicrobial resistance develops," said Wright. "We understand that human health, animal health, and environmental health are closely intertwined. When this resistance in the animal or environmental health sectors occurs, it will, of course, cross over to the human sector. That's why we take it seriously. In Canada, we have many policies to curb bacterial spread. But those policies aren't always adhered to or don't exist in many parts of the world, so it's still a major issue." 

Wright estimated that improving the molecule's stability and efficacy in animal models will take at least 5 to 10 years.

The research was supported by the Canadian Institutes of Health Research, the German Research Foundation/Deutsche Forschungsgemeinschaft, and the National Institute of General Medical Sciences of the US National Institutes of Health. Wright and Bogoch reported having no relevant financial relationships. 

Evra Taylor is a widely published freelance medical writer and reporter with 20 years' experience covering a broad range of therapeutic sectors, including family health, cardiology, psychiatry, ophthalmology, and dermatology.