The biological signal transduction process is the means by which external signals are incorporated into information that directly or indirectly alters gene expression and ultimately, phenotype. The hierarchical structure of signal transduction processes is a topic of intense research. Microbial quorum sensing (QS) is responsible for a variety of phenotypes and is rich in diversity and modes of action. As such, quorum sensing represents a “guide” for learning how signals can be translated into altered phenotype.

 

As microbial communities occupy a confined space over time, concentrations of extracellular signaling molecules accumulate, providing stimulus for unique and varied cellular responses as well as protection from competing microbial communities. Referred to as “quorum sensing” for it’s often reported and coincident dependence on high population density, extracellular signaling provides a new basis for control over molecular and cellular processes as well as population behavior, perhaps in a manner more consistent with that of native machinery. Among behaviors guided by QS are the establishment and persistence of bacterial infections.

Our laboratory has uncovered many of the molecular features of the QS autoinducer-2 (AI-2) system using traditional methods that probe bacterial physiology and by exploiting newer princples of biofabrication. That is, we employed electrodeposition methods to assemble complex biological subsystems onto specific sites on microfabricated devices and within microfluidic channels via programmable electrical signals. We have also used genetic engineering techniques to create signal activated fusion tags that covalently link proteins to the device/bio interface. We have designed and synthesized "biological nanofactories" that provide small signal molecule generation at the surface of targeted and captured cells - enabling programmable control of cell function.

Using these methods, we have discovered attributes of the natural switching mechanism that can be exploited for developing next generation antimicrobials. That is, we decomposed elements of the QS “switch” via mutation and a mathematical model of the regulatory elements and coupled this understanding with devices designed to appropriately interrogate these molecular features. Finally, we have developed alkyl analogs of AI-2 that elucidate structural detail and have potential for affecting behavior in natural environments. Correspondingly, these serve as the basis for creating next generation antimicrobials that target the communication between bacteria rather than their survival mechanisms.