Superbugs like MRSA have undergone genetic changes to survive antibiotics, and it’s these mutations we usually think of when we talk about antimicrobial resistance. But bacteria also have another survival trick up their sleeves: Some bacterial cells enter a dormant state, becoming so-called “persister” cells. These inactive cells grow either very slowly or not at all, and because most antibiotics work by inhibiting cell growth, they’re useless against them. “Unfortunately, in the clinical practice we do not have antibiotics that act against persisters,” said physician and infectious disease researcher Eleftherios Mylonakis, who led the study.
To find a compound that can kill both growing and persistent MRSA, Mylonakis and his coauthors tested around 82 000 synthetic molecules on worms infected with MRSA. They identified 185 compounds that helped keep the worms from dying and narrowed in on two of them: CD437 and CD1530.
CD437 and CD1530 are synthetic retinoids, a type of molecule similar to vitamin A. They kill MRSA, including persister cells, by compromising the bacteria’s membrane. To further investigate the retinoids’ antibiotic potential, the researchers created a variant of CD437 and tested it in a mouse model of MRSA infection. Not only did it stay in the animals’ systems long enough to kill the MRSA, it also caused no signs of toxicity, like liver or kidney damage.
The researchers are optimistic their findings could lead to new drugs to treat MRSA infection. The compounds could be particularly promising candidates for treating chronic infections, which are characterised by high levels of dormant bacteria. But Mylonakis fears current trends in the antibiotic drug development market will make that path a difficult one. “The exodus of many large pharmaceutical companies from the antimicrobial research arena have limited antibiotic drug discovery,” he explained. “We are an academic group. We have some wonderful collaborators, but the next steps cannot be easily done only within academia.”
Mylonakis has experienced the consequences of antibiotic resistance personally. His mother died during a hospital stay, having developed sepsis despite being on multiple antibiotics. While losing his elderly mother was difficult, Mylonakis says he is just as impacted by experiences from his professional life. “As a physician, I am far more motivated from the heartbreaking stories of young people that I see come down with resistant infections and feel that I cannot help them,” he said. This drives him to keep pursuing new antibiotic treatments despite challenges.
These latest drug candidates were identified in collaboration with clinicians, geneticists, physicists, engineers, and chemists from Brown, Harvard, and Emory University. Mylonakis said: “As antimicrobial drug discovery has moved mostly into academia, individual labs cannot perform all the components of this complex work. As a result, collaborations are absolutely necessary.”
Featured image courtesy of NIAID. Article first appeared on Research Gate