Bacterial resistance to antibiotics happens because of evolutionary pressure (Singer, 2014). There are various mechanisms that explain this. One is through the deactivation of the antibacterial drug by the development of bacterial enzymes. Some popular antibiotics like penicillins have structures called beta lactam rings (a moelcular structure) which destroy bacteria by inhibiting bacterial cell wall synthesis. In some instances, some of the bacteria are able to evolve in such a way that it can produce enzymes that counteract the action of the beta lactam ring of penicillins. These enzymes are callled beta lactamases and is just one of the few examples that explain why microorganisms can become resistant to antibiotic drugs.
The Structure of Penicillin G
The diagram below shows the chemical structure of Penicillin G. Penicillin G is a beta lactam antibiotic because of the presence of the beta lactam ring in its structure which is pointed by the red arrow in the picture. The beta lactam ring contains the nitrogen atom attaching itself to the beta carbon relative to the carbonyl groups. I used MS Paint to draw the chemical structures in this blog.
Beta Lactams on Bacterial Cells
The action of the beta lactam antibiotic as an antiinfective medication concentrates on its action to the cell wall of the bacteria. Beta lactam antibiotics such as penicillins act by inhibiting bacterial cell wall synthesis. Within this cell wall are long peptidoglycan polymer chains (Neal 2005). The beta lactam ring of beta lactams reacts with and deactivates the transpeptidase enzyme in this area which is needed by the bacteria to synthesize and repair its cell walls. It prevents the cross-linkage between the peptidoglycan polymer chains that make up the cell wall thus producing antimicrobial effects (McMurry 1998). In the diagram below, Penicillin G as an example of a beta lactam antibiotic prevented the x-linkage of the peptidoglycan chain and this action is possible because part of the structure of the beta lactam ring is that it resembles the D-alanyl-D-alanine of the peptide chains of the wall of the bacteria.
The use of Beta lactams are safe for humans because human cells do not have cell walls. It has cell membranes only. The peptidoglycan layer in which the beta lactams usually act on, can be found in cell walls which is not present in humans.
Antibacterial Drug Resistance and Modifications to Antibacterial Drug Structure to Overcome the Resistance Problem
To explain the earlier example above at the molecular level on bacterial resistance to penicillins, the bacterial enzymes produced deactivates the drug’s beta lactam ring by adding acetyl or phosphate groups to a site specific to the drug. This reduces the drug’s ability to bind to the ribosomes of the bacteria which will also reduce its ability to disrupt protein synthesis (Walsh, 2000).
Another resistance mechanism that bacteria may exhibit is through its manufacture of efflux pumps in which when an antibiotic substance enters the bacterial cell, it is immediately ejected outside by these pumps giving no chance for the substance to change the internal composition of the bacteria. Moreover, antibacterial resistance is also exhibited by enzymatically modifying the drug to block its ability to recognize its target on the ribosome, making the drug ineffective such as in the case of Kanamycins (another example of an antibiotic) through the process of N-acetylation, O-phosphorylation, and O-adenylation.
In addition, some bacteria also make antibacterials ineffective by lowering the drug-binding affinity by switching its amide linkage to ester linkage.
In connection to antibiotic drug resistance, several modifications to drug structures have been done to couteract them. One is through altering the bacteria’s efflux pump by introducing a 3-keto group into the macrolide ring structure of the antibiotic in which an example of this is the drug Clarithromycin. The ketolide will alter the conformation of the macrolactone thus interrupting the effectiveness of the efflux pump.
An Altenative Strategy for Protecting Beta-Lactams
An example of an alternative strategy for protecting beta-lactams is through the use of lactamase inactivators which can be done by combining two antibiotics such as in the case of the drug Co-Amoxiclav, otherwise known as Augmentin. This drug is a mixture of Clauvinate and Amoxicillin. In this strategy, the clauvanate inactivates the beta lactamase thus allowing amoxicillin to perform its antibacterial action by blocking the cross linking of the transpeptidases (Walsh 2000).
Effective antibiotic therapy in the use of the antiinfectives can be heightened if patients follow the prescribed therapuetic regimen. Patients should complete the full course based on doctor's instructions and should not stop taking in the middle of this because they felt better. With proper observance to best practices in this field, effective therapy is likely to be achieved.
References:
McMurry, M. (1998). Fundamentals of Organic Chemistry. 4th Edition. Singapore. Thomson Learning Asia Publishing Ltd.
Rang, H.P., Dale, M.M., Ritter, J.M., and Moore, P.K. (2003). Pharmacology. Fifth Edition. Philadelphia. Elsvier Science Limited.
Singer, E. (2014). Does Evolution Evlove Under Pressure? Qanta Magazine. (online). Available at: www.wired.com/2014/01/evolution-under-pressure/
Walsh, C. (2000). Molecular mechanisms that confer antibacterial drug resistance. Nature. vol. 406. (online). Available at: https://learn2.open.ac.uk/pluginfile.php/1382167/mod_resource/content/1/Walsh.pdf
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