Quieting talkative pathogens
rofessor Dave Lynn and chemistry professor Helen Blackwell have a message for infectious bacteria and fungi: You talk too much. By blocking communication among the interlopers using non-native small molecules, Helen believes that it is possible to block their ability to cause disease. And, Dave may have just the tools needed to get the message through to pathogenic organisms in many situations of critical importance to human health.
But before we discuss their research, let's explore the microbial behavior known as "quorum sensing." Imagine the plight of a lonely pathogenic bacterium entering the human body. It faces a hostile landscape, with the armed guards of the host's immune system constantly on patrol. If you are the bacterium, you have your own armamentarium designed to overcome your host's defenses and induce your host to pass your progeny on to new hosts, but you're tiny and your host is huge. Initially, you'll need to devote all your energy to reproduction if you hope to build the numbers you will need to overwhelm your host quickly and without detection. The last thing you want is to come in with your guns blazing. So you build your numbers quietly, whispering among yourselves until you hear enough whispers back that you are sure you have assembled the force you need (until you sense a quorum, so to speak). Then you launch your attack.
Over the past 30 years, it has become clear that quorum sensing is common among microorganisms, including bacteria and fungi, and is key to their virulence. Microorganisms secrete small signaling molecules that simply diffuse into the environment when cell concentrations are low. Once their concentration reaches a certain threshold level, they will bind to cellular targets, signaling that the time is right to turn on the genes involved in group behaviors, many of which lead to disease.
It is estimated that greater than 80 percent of human infectious diseases involve microbial behaviors regulated by quorum sensing.
This suggests a fundamentally new, and perhaps fundamentally better, way to fight infectious disease: blocking the intercellular communication needed to activate virulence pathways. Current approaches to infectious disease control rely on bactericidal agents, like antibiotics. When a single mutant microorganism survives a bactericidal treatment, it finds itself without competition and able to reproduce unfettered to establish a drug-resistant population.
Bacteria communicate and sense population densities using a language of small molecules (depicted in red) and a process known as "quorum sensing" (left) that controls many aspects of bacterial behavior, including bacterial biofilm formation (right).
On the other hand, a single mutant that maintains its ability to send and receive chemical messages with its neighbors while its neighbors go silent finds itself at no competitive advantage, and may even find itself at a disadvantage if it alone initiates metabolically expensive "group" behaviors. By removing the pressure for micro-organisms to evolve resistance, treatments targeting quorum sensing may finally put an end to the longstanding arms race between drug developers and their adaptable foes.
One more bit of background: Many of the most notorious human pathogens use quorum sensing to organize into biofilms. Biofilms are structured communities of microorganisms adhered to a surface or interface and embedded in an extracellular matrix consisting mainly of polysaccharides (dental plaque is an example). Bacteria in biofilm communities frequently show greater tolerance to antibiotics and host immune defense mechanisms, as well as enhanced virulence compared with their free-living counterparts. From a clinical standpoint, bacterial growth and the formation of biofilms on the surfaces of prosthetic implants can be particularly troubling and difficult to treat.
Which brings us back to the team here at UW-Madison. Helen has expertise in the development of new chemical approaches to disrupting bacterial quorum sensing and virulence in human pathogens. Her laboratory has developed collections of synthetic small molecules that represent some of the most potent inhibitors of quorum sensing (and, thus, biofilm growth) reported to date. These quorum-sensing inhibitors are inexpensive to synthesize, and show minimal toxicity in animal experiments.
Meanwhile, Dave's group has been developing a variety of approaches for the fabrication of polymer thin films that provide new methods for the localized delivery of DNA, proteins, small-molecule drugs, and other agents from surfaces. These methods are low-cost, they provide straightforward control over the compositions and properties of ultrathin coatings, and many of them have been investigated in other biomedical contexts, both in Dave's lab and elsewhere. And of practical relevance, many of these methods can be used to assemble coatings on the surfaces of objects fabricated from
materials having complex geometries and surface structures (e.g., tubes, sutures, fibers, and woven or non-woven fabrics often encountered in clinical settings).
Together, Dave and Helen have demonstrated that these new, materials-based approaches can be adapted for the localized release of quorum-sensing inhibitors from the surfaces of objects, and that these methods, together with more conventional methods for the encapsulation of small-molecule drugs, permit different and complementary levels of control over quorum-sensing inhibitor release.
They have also shown that this surface-mediated approach can be used to inhibit biofilm formation in the pathogenic bacterium Pseudomonas aeruginosa.
Ongoing research will focus on continuing to develop these materials-based approaches to control of bacterial communication both as new tools to study fundamental mechanisms of bacterial virulence and biofilm formation, and as methods that can be adopted readily in personal health and biomedical contexts to treat the surfaces of solid and fiber-based materials to inhibit bacterial biofilm formation and other virulence pathways.
In addition to developing materials that attenuate communication among various types of bacteria, Dave is collaborating with Sean Palecek and his group in CBE to develop approaches to the design of film-coated surfaces that prevent or disrupt the formation of fungal biofilms. These new approaches have the potential to substantially reduce the risk of infection associated with implantable medical devices, and by facilitating further research, could represent the beginning of the end of an arms race with evolving pathogenic microorganisms.