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Antibiotics Mechanisms and Drug-resistance Bacteria

Antibiotics mechanisms and drug-resistance bacteria

The Different Classes of Antibiotics and their Mechanism of Action and Structure

  1. Bacteria and Bacterial diseases

Gram-positive bacteria are characterized by the presence of a single outer lipid membrane and have a thick peptide-glycan layer.  Typical gram-negative bacteria are bound by a double membrane enclosing a thin layer of peptidoglycan between these two membranes in a space called periplasmic space.  (cubist.com, 2014)

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  1. What are antibiotics?

Anti-biotics are chemicals derived usually from bacteria, other microorganisms or chemical synthesis, which slows down or retard the growth of bacteria, thus ensuring that the body’s own defense mechanisms kills them. The body’s immune system is capable of dealing with infections but sometimes, the scale of it may be so much that it gets overwhelmed. In such cases, antibiotics help. Antibiotics are small molecules, often 2000 AU and lesser.

Selman Waksman in 1941 first used the word to describe any chemicals produced by microorganisms that inhibit or retards the growth of other microorganisms. (Clardy, Fischbach & Currie, 2009)  What led to the discovery and study of antibiotics was the discovery of Penicillin. This discovery revolutionized microbiology and the approach towards treatment of bacterial diseases as well as the development of a wide variety of antibiotics include Terramycin, streptomycin etc. The earliest observation of antibiotic effect was in 1870 when Sir John Scott Burdon-Sanderson discovered that the culture fluid covered with a kind of fungus did not show bacterial growth. Over time, more discoveries supported these findings until in 1928 Sir Alexander Fleming isolated an antibiotic for the first time. This was  Penicillin, which was isolated,  from the fungus Penicillium notatum after observations that the growths of this fungus on bacterial plates killed the growth of bacteria. This antibiotic proved dramatically successful in combating syphilis, and tuberculosis.(History of antibiotics, n.d.)

  1. Synthesis of antibiotics

Antibiotics are synthesized from the same chemical blocks that are used for the synthesis of proteins, fats, and carbohydrates. The pathways are similar. They include protein synthesis, modifications of some amino acids, and post-translational modifications. The genetics behind antibiotic biosynthesis is more complicated as in all probability the genes responsible for this have been obtained by horizontal gene transfer as this set of genes are usually associated closely with those for regulation and resistance.  Hence to pinpoint the original gene source is quite tricky as a considerable amount of gene shuffling and transfer may have occurred over time. (Clardy, Fischbach & Currie, 2009)

( Image from (Clardy, Fischbach & Currie, 2009))

  1. Mechanisms of actions of antibiotics

In general, antibiotics can act on bacteria in several ways. They can target various biosynthesis reactions, necessary for the synthesis of the cell wall, DNA, and protein biosynthesis machinery as well as damage the cellular membranes which destroy the integrity of the bacterial cell. Antibiotics are generally effective against bacterial infections, fungi, and some other parasites but not against viruses. The following  factors affect whether an antibiotic is successful or not :

  1. How well developed is the host’s immunity system
  2. location of infection
  3. The chemical properties of the small molecule including its bactericidal effects.
  4. depends on the age of the bacterial culture or population against which the antibiotic is applied.

There are five major mechanisms of action by which antibiotics inhibit or suppress the growth of bacteria.

  1. Cell wall biosynthesis- Cell walls are critical for the stability and viability of many bacterial especially the gram-positive ones. Some antibiotics slow down the growth of bacteria by interfering with the synthesis of cell walls and preventing the addition of units or components vital for cell wall synthesis. Some directly inhibit peptidoglycan synthesis while others do not allow the peptidoglycan units to get cross-linked together. Others interfere in the transport of these units across the bacterial cell membrane. From the diagram, it can be seen that these units have to cross the cell membrane and periplasmic space before being added to the peptidoglycan layer. Still, others interfere with the synthesis of the other component of bacterial cell walls, the mycolic acid (murien residue) (Antibiotic mechanisms, n.d)
  2. Protein synthesis

Other antibiotics interfere in the molecular mechanisms which are a part of vital processes such as protein and DNA synthesis.  Both enzymes, proteins, and new DNA molecules need to be synthesized during replication, transcription, and for the formation of new proteins and enzymes for the metabolic activities of the cell. Some interfere in the protein synthesis by binding to the 30S ribosomal or the  50 S subunit of the ribosome and not allowing the ribosomal complex to be assembled by interfering with the binding of tRNAs to the ribosomal complex. Others interfere with the enzymatic activity of peptidyl transferase of the 50S subunit ribosomal complex and block elongation of the peptide chain.((Antibiotic mechanisms, n.d)

  1. Action on cell membranes.

Another way by which antibiotics can kill bacteria is by making changes in the membrane structure, which may even lead to disruption of the cell.

  1. Nucleic Acid Biosynthesis

Antibiotics can also act by hitting at the core of all the metabolic processes, DNA synthesis. DNA synthesis has to occur for the bacterial cell to divide and propagate. Some of the antibiotics target the enzymes involved in the DNA replication such as gyrates and topoisomerases while others disrupt the DNA structure making synthesis or transcription impossible. Still, others, interfere in the process of transcription by binding to the DNA-dependent RNA polymerases. (Antibiotic mechanisms, n.d)

  1. Types of antibiotics

Antibiotics can be classified in several ways on the basis of this diagram. They can be classified on the basis of the kind of action, on the basis of route of administration and on the range of organisms against which they are effective.

(History of antibiotics, n.d.)

  1. Broad-spectrum and narrow-spectrum antibiotics

Broad Spectrum antibiotics are used to treat a wide range of infections while narrow-spectrum antibiotics are effective only against a narrow range. Broad-spectrum antibiotics can act against both gram-positive and gram-negative bacteria and are thus very powerful. Examples of such antibiotics are ampicillin, amoxicillin, carbapenems, etc. These antibiotics are usually given at the initial stage of an infection when the exact cause is not clear, in case of drug resistance to a narrow spectrum, and when there is an attack by multiple bacteria.  The disadvantage with these is that because of their extremely wide-ranging action, they will kill even good and harmless bacteria in the body.

Unlike broad-spectrum antibiotics, narrow-spectrum antibiotics are used specifically when the causative species have been identified. The use of such bacteria will also cause, less antibiotic resistance. ( uses of antibiotics, n.d.)

Examples of these are: Azithromycin

Clarithromycin, Clindamycin Erythromycin, and Vancomycin.

Based on the kind of action, anti-biotics are of two kinds: Bacteriostatic and Bacteriocidal. Bacteriostatic antibiotics restrict the growth of bacteria by interfering with its proliferation. This it does by targeting the DNA and protein synthesis and other metabolic processes essential for growth and reproduction.  Tetracyclines, sulphonamides are examples of this. Bacteriocidal antibiotics are those which kill bacteria by interfering with the cell wall biosynthesis or interfering with some aspect of the membrane or cell contents. The ultimate result is the rupture of the cell.Examples are penicillins and fluoroquinolones. (History of antibiotics, n.d.)

For research and biochemical studies, the structural classification of antibiotics is extremely important. Antibiotics are classified on the basis of similarities of structures into different groups. Similarly grouped antibiotics usually share commonalities on the kind of function and how they act.

  1. Betalactams: These include penicillins and cephalosporins. They target both gram-positive and gram-negative bacteria.

They interfere in the cell wall biosynthesis in these bacteria by binding to specific proteins (transpeptidases) which are involved in the crosslinking of the peptide subunits of peptidoglycan, which is one of the major constituents of the bacterial cell walls. These proteins are called Penicillin-binding proteins. This class of antibiotics is characterized by the presence of a beta-lactam ring which binds to the active site of the enzymes and thus interferes with it acting on its substrate. The mechanism is through acylation. (Yocum, Rasmussen and Strominger, 1980). Penicillin acts as  a structural analog of the acyl-D-alanyl-D-alanine terminus of nascent bacterial cell wall antibiotics.  (Yocum, Rasmussen and Strominger, 1980).

(Penicillin and other antibiotics, n.d.)

Cephalosporins are similar. They are bactericidal in action and also act in the same way interfering in the cell wall biosynthesis.  (antibiotics types, n.d.)

 

  1. Macrolides – They are produced by fungi and are inhibitors of bacterial protein synthesis. They do this by binding to the bacterial ribosome and thus make it inaccessible to protein synthesis by not allowi9ng the exit of the protein chain from the ribosome. An example is an erythromycin which is derived from Saccharopolyspora erythrea.

 

  1. Tetracyclines– They are the antibiotics with the broadest spectrum of action. Their basic structure consists of four fused rings. The different derivatives differ in the groups around the four rings. They are derived from different species of Streptomyces. They act by interfering in bacterial protein synthesis by preventing the addition of amino acids to the polypeptide chain by blocking the codon-anticodon interaction. (antibiotics types, n.d.)

(Introduction to Drug Action)

 

  1. Synthetic antibiotics: Quinolones, Sulphonamides, Oxalidinones

These are synthetic antibacterials that contain the quinolone nucleus or the( naphthyridone)  nucleus which is ring structures. They target DNA replication and transcription in bacteria. It is an inhibitor of DNA gyrase. E.g. ciprofloxacin.   (LeBel, 1988) They are active against both gram-positive and gram-negative bacteria but more especially gram-negative and especially P. aeruginosa. (LeBel, 1988)

Sulphonamides are synthetic and some have antibacterial activity when it is converted to its active form (Sulfanilamide). The sulphonamide group acts as an analog of a component required for folic acid biosynthesis and hence it deprives the bacteria. OXalidinones are also synthetic compounds displaying antibacterial activity such as LInezolid. They have five-membered oxazolidinone rings and are also protein synthesis inhibitors. (Steane,2014)

  1. Aminoglycosides

They were responsible for the term antibiotics being coined. The most famous one is Streptomyces which is active against Mycobacterium tuberculosis. They are also inhibitors of bacterial protein synthesis and are composed of amino sugars linked together by glycosidic bonds. They are active against both gram-positive and gram-negative bacteria. Streptomyces  modifies the shape of the 30 S ribosomal subunit and creates errors in  the ability of enzymes to read the mRNA properly

Image source: (Introduction to Drug Action,2014)

 

  1. Glycopeptides such as vancomycin. They inhibit certain steps in the biosynthesis of murein which is required for the synthesis of peptidoglycan. They are the fermentation products of certain microorganisms. (antibiotics types, n.d.)

Problems Associated With the Misuse of Antibiotics

The power of antibiotics has led to gross overuse which can have serious consequences on human health. Antibiotics have been misused in the following cases:

  1. Treatment of viral respiratory illnesses, viral conjunctivitis, etc even without a diagnosis
  2. Excessive use of oral antibiotics for ear infections.
  3. use for curing eczema, urine in blood, etc.

Reports show that antibiotic overuse and misuse is a serious issue in the US, especially in the South East. It has also been reported that antibiotic resistance owing to misuse is a serious issue worldwide with 25000 people dying from antibiotic-resistant bacterial infections in 2012 only (what are antibiotics, how do they work, 2013), and the increase in bacterial resistance is associated with the increase in consumption of antibiotics over preceding years.

Using antibiotics against viral infections such as cold, bronchitis, sore throat etc is useless there is a bacterial infection detected alongside. Even with normal usage of antibiotics, there are side effects such as diarrhea, nausea and feeling sick and accompanying infections of the mouth and the genital areas. Antibiotic usage can also lead to rarer side-effects such as kidney stones, abnormal blood clotting, blood clotting, and deafness. (what are antibiotics, how do they work, 2013) In addition, allergic reactions may also occur such as rashes, itching, breathing issues and they may also interfere with other medicines or remedies, if you take them without medical advice.

Hence, antibiotics have to be taken only when absolutely necessary as it can impact the good bacteria living within you. Hence, ideally, it should be used only when absolutely necessary and only when it is known that the cause of the illness is a bacterium.

If normal usage of antibiotics can have such effects, it is easy to imagine the consequences of using antibiotics above the normal usage.  Using antibiotics for the wrong reasons may result in adverse reactions owing to the drug’s action in the body. Some of these effects are very severe and may not be recognized initially as a response to misuse of antibiotics. These include neurological and psychological effects including anxiety, agitation, psychosis, the toxicity of the Central Nervous System. (Arason and Sigurdsson, 2010)

Occurrence and Mechanisms of How Drug-Resistant Bacteria are Created

Even though the discovery and development of anti-biotics have made a huge impact on the treatment of bacterial diseases, the excessive and widespread use of antibiotics has also resulted in the occurrence of drug-resistant mutant forms of bacteria. This is due to selection pressure. Scientists investigated and found that this kind of drug resistance was a result of acquiring of foreign genes conferring antibiotic resistance either via plasmids or transposons and these can be exchanged between different bacteria through horizontal gene transfer.  The resistance to bacteria may be in the following ways:

  1. Production of enzymes that destroy the critical core structure of the antibiotic
  2. Change in the affinity of the antibiotic for its target site or protein
  3. Antibiotic is unable to reach its target site of action in gram-negative bacteria (cephalosporins, 2014) (penicillin, n.d.) (Galatti, et al. 2005) (Hueston, 1997)(Little et al,1997)

Discussion of a Case of Drug-Resistant Bacteria in Detail

One of the most famous cases of drug resistance exhibited by bacteria has been the development of MRSA in hospitals. These strains are responsible for many dangerous infections acquired during hospital stay such as skin and tissue infections, pneumonia acquired from the community, blood infections acquired through the use of instruments such as catheters and pose a huge challenge as they offer resistance to nearly all the effective antibiotics known (which are a wide range and which act at different levels) with the exception of Vancomycin. The expansion of a methicillin-resistant S. Aureus lineage USA3000 took place in 1990 and it resulted in the loss of several other S. Aureus strains which were less drug-resistant.  It is believed that changes in the genetic lineages of these strains were responsible for the spread of MRSA. One such major factor has been postulated to be the acquiring of a gene speG by the bacterium which confers resistance to toxic polyamines produced by the human skin, which thus increased the level of their fitness by several amounts as they were able to colonize more easily, stick to host tissues and improved resistance. The speG may have been acquired by the horizontal transfer of a genetic island, arginine catabolic mobile element ACME 31 KB LOCUS from the closely related S.epidermidis which shows an almost exact similar island. (Planet et al., 2013)

 

List of References:

Arason, V. and Sigurdsson, J. (2010). The problems of antibiotic overuse. Scandinavian journal of primary health care, 28(2), pp.65–66.

Archive.bio.ed.ac.uk, (n.d.) Penicillin and other antibiotics. [online] Available at: http://archive.bio.ed.ac.uk/jdeacon/microbes/penicill.htm [Accessed 6 May. 2014].

Biotopics.co.uk, (n.d.) antibiotics types. [online] Available at: http://www.biotopics.co.uk/g11/antibiotic_types.html [Accessed 6 May. 2014].

Clardy, J., Fischbach, M.,  and Currie, C. (2009). The natural history of antibiotics. Current Biology: CB, 19(11), p.437.

Cubist.com, (n.d.) gram positive bacterial infections. [online] Available at: http://www.cubist.com/products/gram-positive#sthash.OIXjMbk1.dpuf [Accessed 6 May. 2014].

Elmhurst.edu, (2003). Introduction to Drug Action. [online] Available at: http://www.elmhurst.edu/~chm/vchembook/654antibiotic.html [Accessed 6 May. 2014].

Explorable.com, (n.d.). History of Antibiotics – The Discovery by Alexander Fleming. [online] Available at: https://explorable.com/history-of-antibiotics [Accessed 26 May. 2014].

Galatti L, Giustini SE, Sessa A et al.  ( 2005). “Neuropsychiatric reactions to drugs: an analysis of spontaneous reports from general practitioners in Italy”.Pharmacological Research 51 (3): 211–6.doi:10.1016/j.phrs.2004.08.003PMID 15661570.

Hueston, W.J. ( 1997). “Antibiotics: neither cost effective nor ‘cough’ effective”. The Journal of Family Practice 44 (3): 261–5. PMID 9071245

LeBel, M. (1988). Ciprofloxacin: chemistry, mechanism of action, resistance, antimicrobial spectrum, pharmacokinetics, clinical trials, and adverse reactions. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy, 8(1), pp.3–30.

Life.umd.edu, (n.d.). BSCI 424 Pathogenic Microbiology — Mechanisms of Antibiotic Action and Resistance. [online] Available at: http://www.life.umd.edu/classroom/bsci424/Chemotherapy/AntibioticMechanisms.htm [Accessed 26 May. 2014].

Little P, Gould C, Williamson I, Warner G, Gantley M and Kinmonth AL (1997). “Reattendance and complications in a randomised trial of prescribing strategies for sore throat: the medicalising effect of prescribing antibiotics”. BMJ 315 (7104): 350–2.doi:10.1136/bmj.315.7104.350PMC 2127265.PMID 9270458.

Medical News Today, (2013). What Are Antibiotics? How Do Antibiotics Work?. [online] Available at: http://www.medicalnewstoday.com/articles/10278.php [Accessed 26 May. 2014].

Planet, P., LaRussa, S., Dana, A., Smith, H., Xu, A., Ryan, C., Uhlemann, A., Boundy, S., Goldberg, J., Narechania, A. and others, (2013). Emergence of the Epidemic Methicillin-Resistant Staphylococcus aureus Strain USA300 Coincides with Horizontal Transfer of the Arginine Catabolic Mobile Element and speG-mediated Adaptations for Survival on Skin. mBio, 4(6), pp.00889–13.

Steane, R. (n.d.) Types of antibiotics. [online] Biotopics.co.uk. Available at: http://www.biotopics.co.uk/g11/antibiotic_types.html#Macrolides [Accessed 6 May. 2014].

Srspharma.com, (n.d.). Narrow Spectrum Antibiotics : Uses, Advantages, Disadvantages & Products. [online] Available at: http://www.srspharma.com/narrow-spectrum-antibiotics.htm [Accessed 26 May. 2014].

Uic.edu, (n.d.) CEPHALOSPORINS. [online] Available at: http://www.uic.edu/pharmacy/courses/pmpr342/itokazu/cephalosporins.html [Accessed 6 May. 2014].

Yocum, R., Rasmussen, J. and Strominger, J. (1980). The mechanism of action of penicillin. Penicillin acylates the active site of Bacillus stearothermophilus D-alanine carboxypeptidase. Journal of Biological Chemistry, 255(9), pp.3977–3986.

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