Can A New Type Of Antibiotic Help Treat Lyme Disease?

Researchers at Harvard Medical School have identified a new family of proteins involved in the synthesis of bacterial cell walls. This study found that shape, elongation, division and sporulation (SEDS) peptidoglycan proteins have a major part in the formation of bacterial cell walls. For decades it was thought that penicillin-binding proteins (PBP's) were the only set of enzymes that worked in complexes to build the cell wall. Now it appears there are two sets of enzymes working in two different systems. The researchers findings entitled, "SEDS Proteins are a Widespread Family of Bacterial Cell Wall Polymerases" were published in Nature, International Weekly Journal of Science, on August 15, 2016. [1] Perhaps this discovery will lead to new treatment for Lyme Disease.

But First, Some Background

All living organisms (except viruses) have cells. Cells are the basic "building blocks of life." All cells have an outer envelope comprised of membranes. Human cells have a semi-permeable membrane, while bacterial cells contain peptidoglycan, which gives their cells a more rigid exoskeleton. The cell wall plays a critical role in helping bacteria survive within a hostile environment--it is like the bacteria's coat of armor. [2]

In the 1950's scientists first began to understand that penicillin cured infections by blocking the proteins that bacteria use to build their cell walls. By the 1980's scientists discovered the mechanism by which the cell wall linked chains of sugars and peptides together into peptidoglycans(PG). They named these molecules "penicillin-binding proteins" (PBP) for the drug that was able to block them.

As Dr. Judy Stone explains, "The most commonly used classes of antibiotics, penicillins and cephalosporins (like Keflex), work this way. Since human cells don't have these rigid walls, our cell growth continues normally. This is largely why this group, called beta-lactams is the safest class of antibiotics." [3]

How The Researchers Made Their Discovery

In 2003 researchers discovered that certain bacteria were capable of growing its cell wall even in the absence of penicillin-binding proteins. Some researchers were intrigued by the "missing polymerase," sometimes called the "moonlighting enzyme." One of those researchers was Tsuyoshi Uehara a co-author of the SEDS paper. Tsuyoshi suspected that the missing enzyme could be responsible for the cell's shape, elongation, division and spore formation (SEDS). 

To test the hypothesis that SEDS proteins may be involved in cell wall synthesis, Alexander Meeske, HMS graduate student in the Rudner lab and the paper's first author, deleted all the known penicillin-binding proteins involved in polymerizing the cell wall. Yet, SEDS proteins continued to move in much the same way as they always had. The observation made SEDS proteins look like the missing enzymes and more like major players than mere moonlighters.

David Z. Rudner, one of the study leaders said, "Somehow they have to coordinate to build this netlike structure that maintains integrity and expands as the cells grow and divide. That's what makes this so exciting. In this modern era of sequenced genomes, we're still discovering new enzymes that work in this pathway."[4] 

Bacteria Come In All Shapes and Sizes, Most Have Cell Walls

Lyme Disease is caused by a corkscrew shaped bacteria called Borrelia burgdorferi(Bb). While Bb was discovered in 1982, little is know about how spirochaetes grow and divide. Scientists at Yale recently discovered the bacteria that cause Lyme Disease elongate by synthesizing peptidoglycan. [5] (This discovery should coordinate nicely with the SEDS discovery at Harvard.)

I asked Alexander Meeske, one of the lead researchers in the SEDS paper whether spirochetes, a class of bacteria that includes Borrelia, have SEDS. He said, "yes."

What was especially surprising is the discovery that SEDS proteins are more prevalent in the bacterial cell wall than penicillin-binding proteins. This raises hopes that new antibiotics can be developed to target the SEDS proteins within the cell wall. It could potentially lead to new cures for antibiotic resistant bacteria or chronic persistent infections like C-Diff, syphilis, and leprosy. Unfortunately, for bacterial without cell walls like mycoplasma, treatment for chronic infections will remain difficult.

In the U.S., an estimated 330,000 people will contract Lyme Disease this year alone and approximately 36% of them will have lingering, sometimes debilitating, symptoms after a standard course of antibiotics. Would those patients be helped by new drugs that target SEDS? Alas, it will take years to develop such medications. But, it is a tantalizing possibility.

References:

1. SEDS Proteins are a Widespread Family of Bacterial Cell Wall Polymerases 

2. How the Bacterial Protective Shell is Adapted to Challenging Environments.

3. Pathway to Novel Antibiotics May Be New Family of Bacterial Cell Wall Builders.

4. New Family of Bacterial Cell Wall Builders

5. Lyme Disease and Relapsing Fever Borrelia Elongate Through Zones of Peptidoglycan Synthesis that Mark Division Sites of Daughter Cells.

Further Reading:
-Chemometric Analysis of Bacterial Peptidoglycan Reveals Atypical Modifications That Empower the Cell Wall against Predatory Enzymes and Fly Innate Immunity.