Scientists probe mechanics of how bacteria and antibiotics interact down to molecular level

University of Florida Health scientists exploring how combinations of antibiotics can fight resistant bacteria have been awarded an $11.8 million grant for work that could help save the tens of thousands of lives lost yearly to infections that are increasingly plaguing humanity.

The National Institutes of Health, or NIH, grant to the UF College of Medicine and the UF College of Pharmacy will support scientists working to uncover the mechanics of how bacteria and antibiotics interact, down to the molecular level.

READ MORE: Researchers identify new tools for anti-Acinetobacter drug development and AMR preparedness

READ MORE: Harnessing big data helps scientists hone in on new antimicrobials

That mechanistic knowledge has become crucial as bacteria become ever-more resistant to antibiotics. Few pharmaceutical companies are developing new antibiotics, leaving scientists to find novel methods to make older drugs more effective when used in combination.

Call to arms

Accordingly, the National Institute of Allergy and Infectious Diseases, under the NIH, solicited competitive proposals in a “call to arms” to address the crisis, UF Health researchers said.

“It’s very clear on these serious infections with antibiotic-resistant bacteria that monotherapy cannot work,” said Jürgen Bulitta, Ph.D., a co-principal investigator on the project at the UF Research and Academic Center at Lake Nona, Orlando. “Using one antibiotic at a time, you cannot win. You must tag-team with more than one drug to have any chance against serious infections.”

The hope is to ‘dial in’ these antibiotics using newfound insight from the laboratory. It’s like understanding an enemy’s weaknesses to form a battle plan that takes advantage of those chinks in the armor. What receptors on bacteria are best targeted by antibiotics? What precise dosages in a drug cocktail will kill a bacterial population without resistant stragglers surviving to multiply?

Deadliest bacteria

Bulitta and UF Health researcher and co-principal investigator George L. Drusano, M.D., a professor and director of the UF College of Medicine’s Institute of Therapeutic Innovation, will examine two of the deadliest resistant bacteria, Acinetobacter baumannii and Klebsiella pneumoniae.

The bacteria are often found in hospitals, usually infecting patients with weakened immune systems. They are adept at finding genetic adaptations to elude the drugs hunting them.

“These bacteria are not only multi-resistant to antibiotics, they’re also hypervirulent,” said Drusano. “They have turned into really nasty, nasty bugs that wreak havoc on patients’ bodies and too often kill them. We have some great antibiotics. But we need to optimize them and find new approaches that will cure people and get them out of the hospital.”

Hollow fiber infection model

The researchers are using advanced computer modeling techniques and in vitro (outside-the-body) testing, such as a relatively new method called the hollow fiber infection model.

This technique uses a collection of hollow fibers 200 microns in diameter — roughly twice the thickness of a human hair — to culture cells and bacteria. The method reproduces what happens in the human body and helps scientists measure how bacteria respond to drugs and develop resistance.

These bacteria reproduce and evolve in rapid cycles of life and death as short as 20 to 30 minutes, and generations of reproduction are achieved in days. A severe infection might generate billions of bacteria in the lungs, making it highly probable that a beneficial bacterial adaptation will get a toehold, defanging an antibiotic.

Resistant bacteria

Even with a patient’s natural immune defense and antibiotics, Bulitta said, bacteria are reproducing so rapidly, “it’s a near certainty you will still have 100 to 1,000 resistant bacteria remaining in severe lung infections.”

Multidrug therapy seeks to reduce the population of that bacteria with one antibiotic regimen, then hitting it with a second or third using different drugs. This can reduce bacterial numbers before the superbugs can again adapt new protections.

“It’s a game of cat and mouse,” said Bulitta, a professor and The Perry E. Foote Eminent Scholar Chair in the UF College of Pharmacy’s Department of Pharmacotherapy and Translational Research.

UF Health is leading this multicenter investigation. Other participants include researchers at Case Western Reserve University in Cleveland; the Children’s Hospital of Los Angeles, Monash University in Australia; St. Jude’s Children’s Research Hospital in Memphis; Northern Arizona University in Flagstaff, Arizona; and the University of Central Florida in Orlando.