In the ongoing battle against antibiotic-resistant bacteria, MSU researchers have made a discovery that could reshape how we target deadly pathogens like staph infections.
taphylococcus aureus, commonly known as 'staph,' is a group of bacteria that are frequently found on the skin and in the noses of healthy people. While many types of staph are harmless, some can cause serious infections. One particularly dangerous strain is MRSA, or methicillin-resistant Staphylococcus aureus, which is resistant to many commonly used antibiotics. MRSA and other staph infections can range from mild skin conditions to life-threatening blood infections.
A new study conducted by researchers from MSU's Department of Microbiology, Genetics, & Immunology, or MGI, led by recent MGI PhD graduate Troy Burtchett, reveals that this bacterium possesses a surprising level of metabolic redundancy, allowing it to survive even when key enzymes are knocked out. However, when two specific enzymes are removed, staph doesn't infect its host as readily, an insight that could lead to the development of entirely new classes of antibiotics.
The research was supported by a grant from the National Institutes of Health.
At the heart of the research, which was recently published in mBio , is a class of molecules called isoprenoids, which are essential for bacterial survival. These molecules are involved in everything from pigment production to respiration and cell wall synthesis.
Traditionally, an enzyme called IspA was believed to be solely responsible for producing one of the building blocks of isoprenoids called short-chain isoprenoids. But when researchers created staph mutants without the gene, ispA, that encodes for IspA, the bacteria continued to survive—an unexpected result that launched a deeper investigation.
"So how in the world is a mutation in ispA viable? How can the cell tolerate that?" Burtchett asked. "That's really what started this project off. It was really just a basic science investigation."
Burtchett works in the lab of MGI associate professor Neal Hammer . Together, they hypothesized that another enzyme might be compensating for the loss of IspA. They turned their attention to HepT, another enzyme present in staph and in the same class as IspA, and discovered that it was participating in previously unrecognized pathways, including the synthesis of a molecule essential for respiration.
With this new information, they concluded that HepT must be compensating for the missing IspA by producing the short-chain isoprenoids.
To test their theory, Burtchett, Hammer, and MGI doctoral student Jessica Lysne engineered a double mutant lacking both ispA and hepT, the gene that encodes the corresponding enzyme, HepT. Surprisingly, the bacteria were still viable, suggesting the existence of a third, unidentified enzyme that compensates for the loss of the other two.
"One of the conclusions is that there is an incredible level of redundancy in isoprenoid synthesis in S. aureus," said Burtchett. "This has never been demonstrated before."
This redundancy could be a widespread phenomenon. Isoprenoid synthesis pathways are highly conserved across bacterial species, meaning the findings could apply to other pathogens such as E. coli and Pseudomonas.
The implications for antibiotic development are significant. Antibiotic resistance is on the rise and is becoming an increasing concern, as microbes find ways to thwart existing antibiotics, and resistance to one drug can confer resistance to others in the same class. By identifying new, previously untargeted metabolic pathways, researchers hope to develop drugs that bacteria haven't yet evolved defenses against.
"If it's new, there's probably not existing resistance to it," Burtchett said. "It might be more difficult to gain resistance to it, and you can get more use out of that antibiotic."
Looking ahead, the team hopes their findings will inspire further research and drug discovery efforts.
"Dr. Burtchett's findings open exploration into several new areas of research, the most relevant being the identity of the third short-chain isoprenoid synthesis enzymes," Hammer said. "Identifying this enzyme will provide new targets for therapeutic intervention."
