For the first time in 30 years, scientists identified a new class of antibiotics, helping fight against antimicrobial resistance (AMR). AMR, or Antimicrobial Resistance, is when microorganisms, like bacteria, viruses, and parasites, can resist medicines that used to be able to treat them. As a result of drug resistance, antibiotics and other antimicrobial medicines become ineffective and infections become difficult or impossible to treat, increasing the risk of disease spread, severe illness, disability and death. The World Health Organization (WHO) estimates that it causes over 4.5 million deaths annually. It was discovered by a team at McMaster University, led by Dr. Gerry Wright. This compound, lariocidin, is a lasso peptide produced in soil-dwelling bacterium from the Paenibacillus genus, found in Hamilton, Ontario. It was discovered using long-term soil-culturing techniques, in which researchers let native soil bacteria grow over a year, which is significantly longer than usual microbiological protocols, helping them identify slow-growing species that routine screenings miss. Among them, a Paenibacillus strain was found producing a potent antibacterial substance, later identified as lariocidin.
Unlike current antibiotics, lariocidin operates by binding directly to bacterial ribosomes, stopping protein synthesis, which is needed for bacterial growth and replication. While most antibiotics, such as aminoglycosides, macrolides, and tetracyclines, target known sites on a ribosome, lariocidin binds on an unprecedented site, making it a first-in-class agent. This is important because it bypasses the resistance mechanisms that make current antibiotics ineffective, and feed into antimicrobial resistance. Lariocidin has been effective against a range of multi-drug-resistant-organisms (MDROs) including Methicillin-resistant Staphylococcus aureus (MRSA) and Vancomycin-resistant Enterococci (VRE). It is believed to be effective against Gram-negative ESKAPE pathogens, although testing is still ongoing.
In fact, preclinical trials using animal models of inflection, showed that lariocidin could reduce bacterial load without toxicity, showing favorable pharmacodynamics and low cytotoxicity in human cells. It also can resist current resistance pathways, such as β-lactamase enzyme degradation, Efflux pump expulsion, and targets mutations affecting other antibiotic diseases.
Despite promise, lariocidin isn’t ready for clinical use. Its biggest obstacle is production scalability. Because the molecule is naturally made by bacteria, which already make it in small quantities, synthetic and bioengineering methods are being explores. This includes, structural modifications to optimize pharmakinetics and bioavailability, biomanufacturing to make it at a scale, and medical chemistry to increase its stability. They’re also researching structure-activity relationships (SARs) to engineer improved analogs of laricocidin that retain its mechanisms while being easy to manufacture and more potent as well.
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