New Approach Might Provide Potential Treatment for Flesh-Eating Bacteria

Scientists at the Houston Methodist Research Institute say they have found an important target on which to focus for developing a potential Group A Streptococcus (GAS) vaccine or antibiotic to fight it. GAS infections cause several million cases of strep throat every year, but also can lead to more severe infections, such as flesh-eating disease and acute rheumatic heart disease, according to the researchers. By manipulating this target, they hope to either reduce the severity of these infections or clear them up faster. 

Muthiah Kumaraswami, Ph.D., an infectious diseases researcher at Houston Methodist Hospital, is the corresponding author and principal investigator in an article (“Leaderless Secreted Peptide Signaling Molecule Alters Global Gene Expression and Increases Virulence of a Human Bacterial Pathogen”) that appears in PNAS. Dr. Kumaraswami and his team discovered a peptide secreted by the bacteria that signals its neighbors to produce streptococcal pyrogenic exotoxin B (SpeB), which is critical for the development of necrotizing fasciitis, better known as flesh-eating disease. Blocking production of that toxin will be crucial for disease prevention and treatment. 

“We have discovered that GAS uses a previously unknown peptide-mediated intercellular signaling system to control SpeB production, alter global gene expression, and enhance virulence. GAS produces an eight-amino acid leaderless peptide [SpeB-inducing peptide (SIP)] during high cell density and uses the secreted peptide for cell-to-cell signaling to induce population-wide speB expression. The SIP signaling pathway includes peptide secretion, reimportation into the cytosol, and interaction with the intracellular global gene regulator Regulator of Protease B (RopB), resulting in SIP-dependent modulation of DNA binding and regulatory activity of RopB,” write the investigators. 

“SIP signaling causes differential expression of ∼14% of GAS core genes. Several genes that encode toxins and other virulence genes that enhance pathogen dissemination and infection are significantly up-regulated. Using three mouse infection models, we show that the SIP signaling pathway is active during infection and contributes significantly to GAS pathogenesis at multiple host anatomic sites. Together, our results delineate the molecular mechanisms involved in a previously undescribed virulence regulatory pathway of an important human pathogen and suggest new therapeutic strategies.”

“Researchers have known for more than 100 years that GAS uses the toxin SpeB and that it is crucial to disease development,” Dr.  Kumaraswami said. “We did not know, however, what signals the timely production of SpeB by GAS. Now that we have discovered how GAS bacteria communicate with each other to coordinate the production of this toxin, we can target the signaling pathway for vaccine and antimicrobial development.” 

Dr. Kumaraswami says that bacteria interacting and producing toxins is not new. Their communication codes have been characterized for a long time, so researchers know a lot of the classic features in these signals. What's different in what his team discovered is the nature of the language. The GAS communication signal they found lacks a majority of those classic hallmarks. 

“Typically, the signal is quite long and has a number of characteristic features,” Dr. Kumaraswami explains. “The signal we found is compact and doesn't have many of what we traditionally see in other bacterial peptides, which is probably what contributed to the difficulties in finding it for such a long time. There could be similar atypical signals in other bacteria that have been overlooked, as well, so we believe the discovery of this peptide will likely facilitate discovering additional bacterial peptide signals in other pathogens.” 

Researchers can take a number of approaches to target this peptide signal for either antibiotic or vaccine development. They can develop antibodies to target it or a competing peptide to jam the communication path, which would allow them to block toxin production and reduce disease severity. The second approach involves triggering the toxin production at the early stage where the toxin level would be minimal. Then, the host's immune response would be triggered and clear the bacterial infection much earlier.