Body as a Battlefield, Needed Potent Antibiotics

SREEKUMAR RAGHAVAN
We are just eight more years away from celebrating the centenary of the discovery of Penicillin by Alexander Fleming, the first antibiotic to be effective against serious diseases such as meningitis, pneumonia septicaemia, tuberculosis, syphilis and staphylococcus infections. It has saved millions of lives till date.  Basically, the antibiotics conquer the bacteria by interfering with the formation of its cell wall while it is growing. It initially weakens and kills the bacteria.
When a harmful bacterium enters our body, our body becomes a battlefield. And if our antibodies are unable to resist them the antibiotic army is called in. However, as in any army operations, there should be least harm caused to civilians and in this case our cells themselves.

Drug Resistance

Antibiotics has become a potent weapon in the hands of modern medicine practitioners to kill bacteria but some new varieties of bacteria have developed resistance to almost all antibiotics in the physician's arsenal. This is quite worrying. That apart there is also the allegation that most antibiotics are overused causing harm to our metabolism.  
According to Dr Amy Cain of Macquarie University, antimicrobial-resistant organisms kill 700,000 people a year. The Covid-19 related hospitalisations could greatly increase that number as hospitals are hot spots for drug-resistant bacteria.

Dr Cain says Gram-negative bacteria is present almost anywhere and the nasty ones such as E-Coli Pseudomonas Aeruginosa can cause a variety of infections and has become drug resistant. The Gram-negative bacteria has an outer membrane that gives them protection from antibiotics, detergents and antimicrobial enzymes. The class of anti-biotics called polymyxins directly attacks the bacterial cell walls but the weapon is required in doses that are toxic. Even at minimum dose levels it may harm the kidneys.

But Dr Cain believes that they have a solution now in the form of peptides (short strings of amino acids that form the building blocks of proteins). Such peptides with antimicrobial properties can be found in a variety of life forms and can kill microbes directly without impacting the host defence systems. Anti-microbial peptides can strengthen the patient's immune system and can be easily produced on industrial scale. In the lab, they derived it from marine lugworms and was found to be effective against multi-drug resistant gram-negative bacteria. But it turned out to be toxic to cells and destroyed red blood cells (RBC). They tweaked the peptides removing some components or mutating it but keeping the backbone intact. A functional genomic technique called ‘transpon directed insertion sequencing’ was used to prolong the antibiotic action. The results published in the journal Nature Communications was seen to be effective in mouse models but still a long way to go before it gets to human trials.

Haven't Understood the Enemy Yet
Researchers at McGill University believe that all these years we haven't yet understood the enemy and its structure properly even as we used the most potent weapons.  Our individual cells contain specialised compartments such as energy-producing mitochondria known as organelles but bacterial cells were believed to be lacking those as they don’t have membrane-bound organelles. But Stephanie Weber of McGill's Department of Biology has now shown that bacteria indeed have specialised compartments. The organelles are held together by 'sticky' proteins rather than a membrane. Since the bacterial cells were small, Weber's team used an imaging technique-photo activated localisation microscopy-to track the organelle-forming proteins. The discovery by McGill's team may lead to development of a new generation of antibiotics that are urgently needed to combat drug resistance.

Anti-Vitamins

The researchers at the University of Gottingen and the Max Planck Institute for Biophysical Chemistry Gottingen believe that new classes of anti-biotics can be produced from 'anti-vitamins'. The results of the study were published in the journal Nature Chemical Biology. Anti-vitamins are substances that inhibit the biological functioning of a genuine vitamin. The study was conducted on a naturally occurring antivitamin of vitamin B1. Some bacteria are able to produce a toxic form of this vital vitamin B1 to kill competing bacteria. The antivitamin has only a single atom in addition to the natural vitamin in a seemingly unimportant place. The one extra atom in the antivitamins inhibited the functioning of the vitamin. The researchers found that human proteins are able to cope relatively well with the antivitamins and continue with its normal life. This is because human proteins do not bind to the anti-vitamin at all or in such a way that they are 'poisoned'. It was found that antivitamins had adverse impact on bacteria but not on human proteins. This can pave the way of development of 'antivitamin' antibiotics.
The Future
Research has shown the potentially inappropriate use of antibiotics with the intention of preventing the development of bacterial infections. This can also cause drug resistance and also build up toxicity in the body, according to University of North Carolina. We aren’t fully equipped with the right weapons in the war against bacteria especially the drug resistant ones. But new insights on the structure of the bacterial cells itself gives hope of development of more potent antibiotics. After all a war is won only when one understands the strength and weaknesses of the enemy.