Cracking the Code on Drug Resistant Microbes

By Shantanu Bhatt, Ph.D., Assistant Professor of Biology, Saint Joseph’s University

Dr. Shantanu Bhatt and Marisa Egan ’18, a student scholar who is researching E. albertii, a strain of bacteria in the same family as E. coli (photo by Saint Joseph's University)

Dr. Shantanu Bhatt and Marisa Egan ’18, a student scholar who is researching E. albertii, a strain of bacteria in the same family as E. coli (photo by Saint Joseph's University)

Drug-resistant bacteria are on the rise. Over the last decade, countless scientific studies have shown that traditional treatments are becoming less effective in treating a widening spectrum of illnesses. As these treatments fail, it is crucial that we work to understand the biology of these bacteria, how they cause sickness, and how they can be stopped.

Over the course of my career, my research has focused on pathogenic strains of Escherichia coli (E. coli). The bacterium, which exists as a harmless and even beneficial microbe in the intestines of warm-blooded animals, including humans, has also evolved into at least 11 different disease-causing types.

One of those types is enteropathogenic E. coli (EPEC). EPEC belongs to the attaching/effacing (A/E) family of bacteria. These bacteria infect intestinal cells, injecting proteins into the cell to destroy, or efface, their microvilli. Then, they recruit proteins from the effaced microvilli to form pedestal-shaped structures that protrude from infected cells. These protrusions are crowned by tightly attached bacteria.

The disintegration of the microvilli prevents intestinal cells from performing their duty of absorbing nutrients and water, which, in turn, leads to diarrhea. This is especially dangerous for infants – a group that is extremely susceptible to EPEC infections. Alarmingly, due to the emergence of multidrug resistant strains, it is becoming difficult to treat EPEC infections.

Previous studies on EPEC revealed a cluster of genes called the locus of enterocyte effacement (LEE), which is essential for the bacterium to form pedestals and cause disease. I am building on this research to find out how the LEE is regulated. A systematic understanding of the LEE is critical for developing any therapeutic or prophylactic treatments against the bacterium. Specifically, my research focuses on the protein Hfq, which binds to ribonucleic acid (RNA).

Hfq is shaped like a doughnut, with two dissimilar sides. On one side, it binds to a regulatory small RNA (sRNA) and on the other side, it binds to a messenger RNA (mRNA), bringing the two in close proximity of each other and allowing them to pair. Once paired, the sRNA can dictate whether toxic proteins encoded on the mRNA are expressed or not.

In 2016, students working in my lab at Saint Joseph's University were the first to identify three Hfq-dependent sRNAs that regulated the LEE of EPEC. We identified sRNAs that shut off or turned on the production of toxic proteins to modulate the infectivity of EPEC. Since then, we have discovered four more sRNAs.

These discoveries are crucial in the ongoing fight against drug-resistant bacteria. If we can identify regulators that control the virulence of EPEC, we can then develop new drugs against these regulators and curtail bacterial infection. This is especially critical because of the populations affected by the sickness. EPEC-related illnesses occur most often in infants in developing countries, where access to clean water is not available. We must find the means to fight these bacteria so that we can protect the weakest among us. This is central to our mission as a Jesuit university.

Though this research is still in its infancy — developing an effective treatment will take years — I am optimistic about the possibilities, especially because of the work being done by my students. Undergraduate students who study with me have earned several national fellowships, including the Barry Goldwater Scholarship, American Society for Microbiology Undergraduate Research Fellowship, ThermoFisher Scientific Antibody Scholarship, Sigma Xi Grants-in-Aid for Research, and the Sigma Zeta Research Award. Several students have also coauthored research papers with me in peer-reviewed journals.

I have been able to be so productive in the lab only because of these dedicated and diligent students, who have pushed our research to un-chartered frontiers. I’m humbled and inspired by their work and confident in their path forward.