The following article and photo were published on by the Duke Translational Medicine Institute. See the original article here.
Beating Back Multidrug Resistant Bacteria
June 29, 2015
Editor’s Note: This is the first in a series of articles exploring partnerships between basic scientists and clinicians supported by Duke Translational Research Institute (DTRI) Collaborative Pilot Agreements for 2015.
The World Health Organization recognizes antibiotic resistance as a leading threat to human health around the world. If nothing changes, the WHO estimates that by the year 2050, antimicrobial resistance could kill 300 million people and cost 100 trillion dollars.
“This is one of the world’s top health threats and the global need is increasing at a time that new agents are disappearing from the investigational pipeline, particularly agents for the most resistant bacteria,” says Vance Fowler, an expert at Duke in infectious diseases.
With the help of funding from the Duke Translational Research Institute (DTRI), Fowler is collaborating across departmental lines with Duke faculty members Pei Zhou and Eric Toone in an exploration of the efficacy of beating back multidrug resistant bacteria by using chemical compounds known as LpxC inhibitors. These chemical compounds disrupt the formation of Lipid A in the protective membranes around Gram negative bacteria – a novel way of destroying bacteria.
When Zhou and Toone first began working with LpxC inhibitors more than a decade ago, their goal wasn’t to fight nasty antibiotic resistant infections. They were simply following the lead of Christian Raetz, former chair of biochemistry at Duke.
Raetz was an expert in lipid biosynthesis and the formation of biological membranes. He wanted an inhibitor of a key enzyme called LpxC for use in basic studies of biological structure and function. He enlisted Zhou, a structural biologist, and Toone, a chemist, to help him find one.
Raetz died of esophageal cancer in 2011, but his legacy lives on at Duke in more than 200 chemical compounds, known as LpxC inhibitors, that the Duke team came up with over the years. These days, the team’s focus has shifted based on a very important realization: Any one of their LpxC inhibitors might just be the next big thing in treating infections caused by bacteria that no longer respond to any of the antibiotic drugs in today’s clinical arsenal.
A Novel Pathway
“LpxC inhibitors target a pathway that has never been exploited by current antibiotics,” Zhou said. “It should be very effective for multidrug resistant strains [of bacteria].”
“That’s one of the big hooks,” says Toone, who in addition to being a chemist is also Duke’s Vice Provost and Director of the Duke Innovation and Entrepreneurship Initiative (link is external). “The mechanisms that have allowed more and more pathogenic bacteria to outsmart us aren’t expected to help the bugs at all when it comes to treatment with LpxC inhibitors.”
There’s already plenty of evidence to back the idea that LpxC inhibitors might work safely where other antibiotics now fail. In fact, Merck scientists discovered the first LpxC inhibitor back in 1996. That inhibitor seemed to work in mice with E. coli infections, but researchers abandoned it because it didn’t work sufficiently well in other contexts. Later, another company found a broader spectrum LpxC inhibitor. But it was Zhou who made a critical leap, by adding a substituted methyl group in a key location. That chemical modification enhanced the affinity and specificity to make the Duke team’s inhibitors “quite a bit better.” In the last two years, they’ve patented their compounds, giving them greater freedom to study and move them forward.
The researchers have shown in earlier studies, both in lab dishes and mice, that one of their compounds dubbed LPC-058 works well in the fight against Gram-negative pathogens, including E. coli, Salmonella, Chlamydia, Vibrio cholera, Neisseria gonorrhoeae, and more. Ongoing studies with colleagues in France show that LPC-058 rescues mice infected with a lethal dose of the bacteria responsible for the condition commonly known as the plague.
Lab Meets Clinic
Fowler, Zhou and Toone are now turning to drug-resistant, Gram-negative pathogens involved in ventilator-associated pneumonia (VAP).
The DTRI Collaborative Funding helps bridge the gap between laboratory science and clinical science. When Zhou and Toone shared their excitement about working with inhibitors to fight VAP with Fowler, it didn’t take much convincing to get him on their team.
“We’re running out of options. Full stop,” Fowler said in an interview just before making hospital rounds of patients fighting for their lives against bacterial infections.
As the three investigators explain in their proposal for that collaborative funding, VAP caused by multidrug resistant bugs creates long odds for patient survival. They will test the use of three of their candidate compounds against a short list of the most troublesome multidrug resistant pathogens in VAP.
“One of the key aspects of this grant-funded work is to better understand the efficacy of the compounds we’ve made,” Toone said. “We’ve made more than 200 compounds grouped broadly into four classes. What we’d like to do is get a better sense of their efficacy not just against laboratory strains of bacteria, but against actual clinical isolates.”
The DTRI funding is serving a critical role in moving their work from the lab to the clinic. The team, including Zhou, Toone, and Fowler, is one of five to recently receive collaborative grants from the DTRI.
“The reason we are excited about the prospect of this agent being able to treat infections in a variety of settings including pneumonia is because we need alternatives,” Fowler said. “Doctors using antibiotics are like carpenters using tools. A carpenter with one hammer and no other tools won’t be very effective. The same analogy applies with doctors.
“If you have a new class of antibiotic with a new mechanism of action that’s totally different from before, the likelihood that bacteria will be resistant is much less. That’s what really makes this exciting.”
By Kendall Morgan