One of the foundations of the modern medical system has been the discovery and advancement of antibiotics during the past 70 years. The bacteria initially had no answer to these antibiotics and a vast number of diseases have been cured by a host of antibiotics. But bacteria have been very good learners. Generations after generations have shown a step-by-step increase in resistance and now, only a few potent antibiotics alone can cure some of the diseases caused by these resistant stains.
In 1928, Alexander Fleming discovered penicillin from Pencillin notatum, which at that time could kill staphylococcus entirely. The same staphylococcus is now 98% resistant to penicillin. Similarly Enterococcus faecum is 70% resistant to ampicillin. Lots of examples like these can be narrated.
The reason for their resistance is that we, the humans, have been assisting the bacteria for their stunning success against long standing antibiotics in a variety of ways. We misuse or over use antibiotics. The prescribed course isn''t completed. Antibiotics are taken for viral diseases like cold and flue, which do not respond and do not require antibiotic medication. A large percentage of antibiotics is used in livestock, and they are also used in bathing soaps and floor-cleaning liquids.
All these practices don''t kill the bacterial cells entirely and one or two among thousands of these cells remain resistant. The bacteria themselves are wily warriors and these resistant bacterial cells propagate giving rise to an entire stain of resistant organisms.
All antibiotics are obtained from nature. Researchers obtained antibiotics by observing the bacterial susceptibility towards molds in culture. Till the 60s new antibiotics were discovered after which there had been a gap of 35 years and in April 2000 a new kind of clinical antibiotic linezolid was approved. It was a result of information from genome and protein studies.
In the last century among the antibiotics discovered vancompycin was and is the most potent. Today, Vancomycin is the last resort for patients who have not responded to other antibiotics. It is potent against the deadliest strain of bacteria i.e., methicillin resistant Staphylococcus aureus. Vancomycin, like B-lactam antibiotics acts by interfering with cell wall synthesis. Other antibiotics such as erythromycin and tetracycline disrupt ribosomes and sulfonamides interfere with DNA synthesis.
Vancomycin is a glycopeptide group of antibiotic, which interferes with peptidoglycan arrangement in the cell wall of bacteria. Assembly of wall material takes place by sugar units, which are linked together by an enzyme transglyconsidase to form the basic structure. Every other sugar unit along this structure has a short peptide chain attached to it. Each chain has 5 amino acids and an enzyme transpeptidase combines two peptide chains by removing terminal amino acid from one of the chains. The final bond forms between D-alanine and L-lysine. Such linkage forms a thickly woven material of peptidoglycan.
The vancomycin molecule combines with terminal chains and prevents the action of transpeptidase. The molecule behaves like a hand holding a ball (cell) with 5 fingers. The peptide chains are blocked by 5-hydrogen bonds there by stopping proper alignment of peptidoglycan. As a result, a very weak wall is formed and due to high internal pressure the cell bursts, leading to death.
But the new resistant strains have a couple of strategies to overcome vancomycin. One mechanism is the alteration of terminal amino acid by substitution. This makes the vancmycin hold the cell with only four bonds there by reducing effectiveness and making the drug molecule susceptible to enzyme removal. Sometimes, the bacteria thicken the peptidoglycan layer and reduce the peptide linkage there by making the drug useless.
In 1998 vancomycin resistant S. aureus has been reported which has put the entire pharmaceutical industry into the motions of novel antibiotic discovery. Some new varieties have been obtained e g. Eli Lilly''s LT-333328. Many more are in the waiting. Earlier, drug discovery process identified drug candidates by applying molecules of interest to bacterial cells. But, nowadays new techniques have developed which provide not only good screening but also narrow down the action specificity to a particular action mechanism.
Genomic technologies help researchers know the genetic basis of synthesis of various protein and enzymes by bacteria there by targeting aspects within the bacterial cell. The DNA sequence of organisms can be analyzed stepwise and specific targets can be identified for the drug to show its action.
Specific virulence factors can be isolated and can be targeted using drug molecules. Also, the bacterial RNA can be altered there by making it misread information. The RNA is more susceptible to drug action as it has many sites for drugs to bind. This technique is being used by chemists at Parke Davis against HIV infection.
Though these techniques hold great promise they are still at infancy and bacteria are developing new mechanisms of resistance to counter antibiotics and we are only helping them to do so. It is estimated that about a half of the prescribed quantity of antibiotics is improperly or unspecifically used. Such usages will not only make our ground weaker but also help bacteria with their weaponry and win the biological arms race between humans and bacteria with their most potent weapon - resistance.
About the author:
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The authors are with G Pulla Reddy College of Pharmacy, Hyderabad.