Wenjun Zhang, a professor of chemical and biomolecular engineering at the University of California, Berkeley, is investigating how to promote healthy bacteria in the mouth to reduce cavities. Her research focuses on distinguishing beneficial bacteria from those that contribute to tooth decay by examining gene clusters in the oral microbiome.
The oral microbiome contains hundreds of bacterial species, many of which form plaque on teeth. While previous studies have identified specific species linked to cavities due to acid production, Zhang’s team found that strains within a single species can vary widely in their potential to cause dental problems. Instead of targeting specific species or strains, Zhang’s approach involves scanning DNA sequences—the metagenome—of all oral bacteria for gene clusters associated with cavity formation.
In a paper published August 19 in Proceedings of the National Academy of Sciences, Zhang and her colleagues reported discovering a gene cluster that helps both harmful and beneficial bacteria stick together and form biofilms on teeth. This cluster was present in some strains of known cavity-causing bacteria such as Streptococcus mutans but not all.
Zhang said, “Particular strains belonging to the same species can be a pathogen or a commensal or even probiotic. After we better understand these molecules’ activity and how they can promote strong biofilm formation, we can introduce them to the good bacteria so that the good bacteria can now form strong biofilms and outcompete all the bad ones.”
The study received support from the National Institute of Dental & Craniofacial Research at the National Institutes of Health (R01DE032732). The researchers used an online database containing numerous metagenomic sequences from human volunteers’ oral microbial communities. Graduate student McKenna Yao performed statistical analyses to identify relevant gene clusters and then cultivated bacterial samples for further analysis.
The metabolites produced by these gene clusters are small molecules composed of short amino acid chains (peptides) and fatty acids (lipids). One acts as glue for clumping cells into blobs; another enables chain formation among cells. Together, they help bacteria build resilient communities—biofilms—that adhere to teeth.
This newly identified gene cluster consists of about 15 DNA segments encoding proteins, enhancers, and transcription factors that function as an alternative metabolic pathway. These specialized metabolic networks have previously been important sources for antibiotics in soil bacteria.
Yao stated, “These specialized metabolites enhance survival in certain ways. Many, for example, are antibiotics, so they can kill other bugs, or others are involved in metal acquisition — they help the bacteria monopolize the resources in their environmental niche. Being able to produce these, especially in a microbial community, helps the bacteria boot out the other guy and guard their resources.”
Despite growing interest in secondary metabolites’ roles across human microbiomes—including gut and skin—their functions remain underexplored according to Zhang. Two years ago her group found an antibiotic-producing gene cluster among oral microbes; another discovery revealed sticky molecule-producing genes supporting biofilm development.
Zhang explained that understanding these sticky molecules—called mutanoclumpins—could lead to new strategies for preventing cavities: “We are looking for something which is correlated with cavities, with disease. If one day we can prove that, under certain conditions, this is really a bad molecule you want to prevent, we might develop genetic or chemical inhibitors to inhibit their production… Meanwhile, we also look at other molecules correlated with health…”
One focus is Streptococcus salivarius—a bacterium marketed as an oral probiotic but unable on its own to form strong biofilms on teeth. Adding robust biofilm-forming molecules could improve its effectiveness as a probiotic agent.
“Our future work will be to create a broad map of the collection of these specialized metabolites,” said Zhang.
Yao added: “the best way you can remove the biofilm on your teeth is to brush. We believe that there’s actually a better way of disrupting that biofilm, but we’re just beginning to understand what the complexity is within the mouth.”
Other contributors include Nicholas Zill and Colin Charles Barber (first co-authors), Yongle Du, Rui Zhai, Eunice Yoon and Dunya Al Marzooqi from Berkeley’s Department of Chemical and Biomolecular Engineering; Peijun Lin from Berkeley’s College of Computing Data Science & Society also participated.
