Human health is in large part dictated by our interactions with bacteria. The dangers associated with bacterial pathogens have been appreciated since the 1800's. But we are losing the war against these bad bacteria because bacteria are evolving resistance to known antibiotics far faster than we are developing new antibiotics. Here I propose to address this crisis by developing a new antibiotic strategy that leverages our discovery of mechanosensitive virulence regulators that control pathogenesis independently of growth. All existing antibiotics either kill bacteria or inhibit their growth. The very tool we use to treat pathogenic infections thus gives antibiotic-resistant mutants a huge fitness advantage. Consequently, targeting mechanosensitive virulence regulation could mitigate the rise of resistance, representing a resistance-resistant therapeutic strategy. Our recent identification of a mechanosensor, PilY1, whose disruption eliminates P. aeruginosa virulence without affecting growth, enables us to directly test this promising hypothesis. At the same time as we are growing less capable of controlling pathogenic bacteria, recent studies show that we can no longer simply view bacteria as our foes. Indeed much of healthy human physiology, from gastrointestinal function to diabetes to immune development depends on the symbiotic relationship between the human body and its good bacterial partners. However, we remain woefully bad at manipulating our microbiome. Here I propose a (to my knowledge) completely novel approach to manipulating bacterial populations that leverages my lab's recent discovery that bacteria have a sense of touch that they use to sense and respond to their mechanical environment and my expertise in engineering assays to study bacterial- host interactions in environments that mimic the mechanics encountered by bacteria within humans. Specifically, I propose to quantitatively assay how mechanical forces in the body
My lab recently discovered that bacteria can sense and respond to mechanical forces they encounter in their environment. These forces, such as fluid flow in blood or urine or adhesive forces encountered upon attachment to host cell surfaces, strongly influence the ability of bacteria to colonize new environments and to induce virulence. Here we propose to exploit these new mechanical principles to promote colonization by beneficial commensal bacteria and to develop new classes of antibiotic drugs that manipulate how pathogenic bacteria interact with their hosts without affecting bacterial growth, thereby reducing their susceptibility to the rise of antibiotic resistance.
