INFORM October 2024

LIPID-CENTRIC THERAPIES

inform October 2024, Vol. 35 (9) • 13

THE GRAM-NEGATIVE CHALLENGE CRAB, E. coli, and many other drug-resistant species fall within a category called gram-negative bacteria, which have a mul tilayered cell envelope that makes them difficult to defeat. (The name refers not to the unit of weight but to the scientist, Christian Gram, who developed a test to help classify them in the late 1800s.) “It has been more than 50 years since the last distinct class of antibiotic was launched that is capable of treating infections by gram-negative bacteria,” Bradley said. “At the same time, drug resistance to all existing classes of antibiotics has been on the rise in various gram-negative bacteria for sev eral decades.” Penicillin disrupts the peptidoglycan cell wall, which is present in both gram-negative and gram-positive bacteria. Other types of antibiotics block synthesis of the proteins bac teria need to grow. But the bacteria’s membrane layers have been relatively underexploited as targets. The drug candidate from Roche targets the outer membrane that sits on top of the cell wall in gram-negative bacteria and gives them an extra layer of protection against antimicrobials. Roche’s approach relies on a class of molecule called tethered macrocyclic peptides (MCP). Merck recently called macrocyclic peptides “the next wave of drug discovery” in a corporate article, and they are being explored not only for antimicrobials but cholesterol medicines, cancer therapies, and other applications. The peptides often prompt references to Goldilocks because of their ability to achieve “just-right” func tionality, penetrating cells like small molecules can but retain ing the target specificity of larger molecules. It was the peptide that led Bradley and colleagues to focus on the bacterial membrane, not the other way around. They screened a collection of approximately 45,000 macrocyclic peptides for their ability to kill bacteria, rather than filtering for a specific component of the cell.

While these medicines have been transformative in treating staph, tuberculosis, strep, and a host of other bac terial illnesses, they do not do a thing for others—but doc tors prescribe them anyway. They were used as a last resort in the absence of a diagnosis; sometimes, because patients demanded them. The US Centers for Disease Control and Prevention estimates that one in three antibiotics prescriptions is unnecessary. Overprescribing, combined with excessive use of antibiotics in agriculture and an anemic pipeline of new drugs, provided the opportunity for bacteria to evolve more defenses. “We have virtually exhausted traditional drug discovery resources, such as chemical libraries and finding bacteria- and fungi-derived antibiotics in the environment that can be grown easily in the laboratory,” said Anthony Fauci, then director of the National Institute of Allergy and Infectious Diseases, in a 2018 interview. CRAB is among the most costly and stubborn superbugs that haunt hospitals and nursing homes. It can make peo ple very sick, infecting the lungs, urinary tract, skin, and other parts of the body, but it can also colonize on skin or in the body without causing symptoms, creating another transmis sion pathway. It primarily strikes immunocompromised people, persists on surfaces for days to weeks, and is impervious to most antibiotics. In other words, it is a nightmare in a health care setting. The World Health Organization put CRAB in the top “crit ical” tier of its 2024 bacterial priority pathogens list, noting that critical pathogens earned the label “because of their abil ity to transfer resistance genes, the severity of the infections and disease they cause and/or their significant global burden, particularly in low- and middle-income countries.” Overall, the list covers 24 culprits, including forms of Escherichia coli, Salmonella , Shigella , Neisseria gonorrhoeae , Pseudomonas aeruginosa , and Staphylococcus aureus .