‘Keep the cell wall shut’ model to fight bacterial infection

Even as we discover drugs and molecules to fight them, bacteria quickly mutate, resist

There are about 7 billion humans, while the total number of bacteria is five million trillion trillion

Bacteria have been on Earth for the last 3.8 to 4 billion years. And they have depended on whatever the environment has provided them for carrying on with their lives and reproduction. We humans are late-comers on Earth, roughly about 66 million years ago. Today there are about 7 billion of us (7 followed by nine zeros) while the total number of bacteria is astounding — five million trillion trillion (a five with 30 zeros after it); there are far more bacteria on Earth than there are stars on the universe.

And many of these bacteria feed on us. While some of them are “safe” and even useful for us (the human gut hosts about 100 trillion bacteria, helping us in our growth and development), many others make us ill and even kill us. And we humans have tried various ways to fight these infections using herbs and drugs since ancient times. Dr Rustam Aminov writes in his paper: “A brief history of the antibiotic era: Lessons learned and challenges for the future” ( Frontiers in Microbiology, 8 Dec 2010) that ancient Egyptians tried using poultices of moulded bread against infection and ancient Sudanese skeletons had traces of the antibiotic tetracycline — obviously from some herb they would have used against microbial infections.

A recent course

The day of modern medical treatment is recent. Dr. Hara discovered the compound arsphenamine to fight syphilis in 1909 and Dr. Bertheim synthesised it and called it salvarsan in 1910. And in 1928, Alexander Fleming discovered penicillin, which could kill a large number of infecting bacteria.

Even as we discover more and more drugs and molecules to fight them, bacteria quickly change their genetic composition by mutation and resist the action of the drug. It has thus been a tug of war between scientists and bacteria. We have now come to realise that unless we understand the basic biological steps involved in bacterial infection, this fight cannot be won by us.

It is towards this challenge that microbiologists have been studying the molecular biology of bacteria using the species called

Escherichia coli (

E. coli for short) as the model organism in the laboratory. We now know that bacterial cells are surrounded by a protective cell wall made up of a large sac-like structure called peptidoglycan or PG. The PG that bacteria use to build their cell walls is specific to them alone, and not found anywhere else on earth.

The PG is a baglike structure which is made of sheets of two sugar molecules, NAG and NAM, linked together as long chains. These sheets are cross-linked or stapled together to form a continuous layer around the bacterial cells. Therefore, as the bacterium grows in size, this PG bag also has to expand. That means the stapler has to be opened, new material incorporated and the bag stapled again into compactness for successful bacterial growth.

Key step

An important step towards this has been made by Dr. Manjula Reddy and her colleagues at the Centre for Cellular and Molecular Biology (CCMB) at Hyderabad. Her group has been studying the basic biology behind how the bacterium builds its cell wall, how the bag opens for growth, and what molecules help in opening the bag. Her group has identified a particular class of enzymes, which are responsible for unstapling the PG bag (see their publications: Singh et al., Mol. Microbiol., 2012; 86(5), 1036-1051; Singh et al., PNAS, 112, 10956-10961; Chodisetti et al., PNAS, April 2, 2019; https://doi.org/10.1073/pnas.1816893116). They further showed that if any or all of these enzymes are removed from the bacterium (using genetic engineering methods), the PG bag does not open, starving the bug to death.

What does this mean? If we can find molecules or methods to inhibit these enzymes, and thus arrest the infecting bacterium from making its protecting cell wall, we will have found a way to overcome infection and offer safety.

A differing approach

Incidentally, the classical antibiotic, penicillin, inhibits the enzymes which help in re-stapling the once-opened cell wall, thus weakening the bug and killing it. While this approach is a “do not close the wall” one, the CCMB approach is a “keep the cell wall shut and never open it” one. The currently popular class of antibiotics, called the fluoroquinolones (such as ciprofloxacin), acts not on the cell wall, but inhibits the enzymes that allow the DNA of the bacterium to open up and replicate itself. These drugs thus inhibit the reproduction and repair of genes of the infecting bacteria.

dbala@lvpei.org