New Approach Could Be Silver Bullet Against Antibiotic Resistant E. Coli & Other Gram-Negative Bacteria

Some types of bacterial infections are notoriously tough to treat — and it's not all due to antibiotic resistance. The bacteria themselves are rugged and hard to penetrate with drugs.

New research may have solved that problem. A group of researchers from the University of Illinois has figured out how some compounds get into E. coli and similar bacteria, and how they can use this information to build other compounds that they get in, too.

The research, by Paul J. Hergenrother and colleagues was published May 10th in Nature.

One Tough Type of Bacteria

A couple of months ago, the World Health Organization published a list of bacteria for which new antibiotics are urgently needed

The most urgent needs are for several gram-negative bacteria — bacteria that do not stain pink with Gram stain — like Escherichia coli, Acinetobacter, Klebsiella and Pseudomonas aeruginosa. These gram-negative bacteria have a specialized cell wall that doesn't absorb the stain.

Gram-negative bacteria are prone to developing resistance to most of the antibiotics we have available and run rampant in healthcare facilities. That's especially dangerous — these facilities treat very sick people with lots of antibiotics that promote resistance, and these resistant bacteria can hide out in medical equipment, ready to be passed on to the next sick person.

Antibiotic resistance isn't the only challenge these gram negative bacteria present.

The gram-negative bacteria's rugged outer cell membrane is hard for drugs to penetrate, a fact that's practically stalled the development of antibiotics against them.

"These microbes have an outer membrane that is basically impermeable to antibiotics or would-be antibiotics," Hergenrother said in a press release from the University of Illinois Urbana-Champaign.

Getting Through to Gram-Negative Bacteria

The research team found that some drugs and other compounds were getting into the gram-negative bacteria through a unique portal, a pore-shaped protein that spans the bacteria's outer membrane, called a porin. The porins let through amino acids — the building blocks that make up proteins — and other small compounds the bacteria need to live.

The team modified 180 natural products of plants and microbes by adding an amine — a grouping of elements that contained nitrogen and hydrogen molecules in a particular configuration — not unlike the components of amino acids.

New Approach Could Be Silver Bullet Against Antibiotic Resistant E. Coli & Other Gram-Negative Bacteria — Structure of an amine used to transform gram-positive antibiotics to drugs that can also kill gram-negative microbes. *Image via L. Brian Stauffer*

By engineering different configurations of the compounds, the investigators discovered three key traits required for antibiotics to gain access into gram-negative cells. The team found that a compound must have an amine group, it must be relatively rigid to get through the porin opening, and it must have "low globularity" — it must be structurally flat, more circle than globe.

They applied their three guidelines to modify deoxynybomycin, a natural antibiotic that is active only against gram-positive organisms. The new drug penetrated gram-negative bacteria and killed a variety of the bacteria, except for Pseudomonas aeruginosa. It also showed antibacterial activity against a gram-negative multi-drug resistant strain of E. coli.

"Now, we know how to make collections of compounds where everything gets in," said Hergenrother.

Despite the fact that only about one in 200 random compounds that penetrate gram-negative bacteria are also likely to kill the bacteria, the scientists are optimistic that their approach will be fruitful, as Hergenrother said, "these are workable odds."

Findings from the new study and that positive outlook may help us meet the urgent need for new drugs to treat gram-negative bacteria.