SCIENCE

IN SOCIETY INVESTIGATION

AN APPLICATION OF SCIENCE THAT HAS AN EFFECT ON HUMAN HEALTH













A REVIEW INTO THE POSSIBLE METHODS TO PREVENT THE DEVELOPMENT OF ANTIBIOTIC
RESISTANCE







SUBMITTED FOR ASSESMENT PURPOSES










CATHAL BUCKLEY
CUS
2019





BACKGROUND:
Since the discovery of penicillin by Alexander Fleming in 1928, antibiotics have truly
revolutionised the course of medicine and has allowed Health Care Professionals to treat
bacterial infections that were once life threatening. For example, meningitis and endocarditis.
This begs the question, how do antibiotics work?

Antibiotics work in two ways; the first way is by inhibiting the growth of bacteria and killing
them, these types of antibiotics are called bactericidal drugs. Some antibiotics slow down the
growth/ multiplication of bacteria these are called bacteriostatic drugs and they work by
slowing down metabolic reactions in the body for example, enzyme activity. Figure 1 shows a
simplified diagram of a typical bacteria cell, the phospholipid bilayer of the cell is comprised up
of a cell membrane and a peptidoglycan bilayer (cell wall). Bactericidal antibiotics work by
either inhibiting the cell membrane which bursts the cell membrane leading to leakage and the
disruption of osmotic balance. Others work by inhibiting the cell wall synthesis which leads to
the death of the cell wall. The second type of antibiotics that I have previously mentioned are
bacteriostatic antibiotics. These do not inhibit cell walls or inhibit cell membranes but rather
these slow the growth of bacteria so our immune system has time to effectively kill the bacteria
on its own.

When an antibiotic is used to treat a bacterial infection, the bacteria are killed either by
Bacteriostatic methods or Bactericidal methods. However, certain strands of bacteria have
evolved and have developed a mutation (a sudden change in a gene) this changes the genetic
make-up of the gene which allows it to be not afflicted by the antibiotic. This bacterium can
then pass on its genetic material to other bacteria causing the antibiotic resistant bacteria to
multiply rapidly. Certain strands of bacteria have advanced so much that they are now resistant
to all antibiotics. For example, MRSA (methicillin resistant staphylococcus aurous) and C.
difficile. If bacteria continue on to evolve the number of “superbugs” as they are so called will
only increase. In this research study I seek to investigate the possible methods to prevent

Youtube - Armando Hasudungan 2014 Figure 1 – a simple diagram of a bacterial cell

 antibiotic resistance to hopefully inhibit the rapid development of “superbugs” or multi-drug
resistant bacteria (MRB).



IMPACT ON SOCIETY

Antibiotic resistance poses a major risk for human health. Death by antibiotic resistance in 2017
was over 23,000 in the US. Dr. Margret Chan, former WHO Director General said “A post-
antibiotic era means, in effect, an end to modern medicine as we know it”. If Antibiotic
resistance continues to rise it will become increasingly difficult and expensive to treat
infections which will place a major burden on society. It is predicted that in just 20 years from
now superbugs could kill more people a year than cancer. In October 2017 the HSE published a
National Action plan on antimicrobial resistance which outlines Ireland’s 5 key strategic
objectives to tackle antibiotic resistance.

Figure 3 – shows the deaths by antimicrobial resistance on the y axis and time on the x
figure 2 – shows the deaths from antimicrobial resistance infections in 2050. axis. Showing the amount of people killed by superbugs is greater than Cancer
Youtube – Kurtsgesagt - 2018












METHOD ONE: THE USE OF BACTERIOPHAGES TO REPLACE ANTIBIOTICS

WHAT ARE (BACTERIO)PHAGES? HEAD

Bacteriophages or phage’s for short are microscopic viruses which consist of

a head containing the genetic material of the phage which sits on a tail with
leg like fibres which assist with the implantation phage’s DNA into the host TAIL

cell. Bacteriophages attack Bacteria and so pose no threat to humans but

they are responsible for the deaths of up to 40% of all marine surface TAIL

bacteria. Phage’s begin by attaching to the host cells receptor sites. Each FIBRES

receptor site is unique and so only one type of phage can target one type of
bacteria. After this the phage’s form a hole in the host cell and viral DNA FIGURE 1 – structure of a Bacteriophage

enters the host cell. The viral DNA with the help of the host cell organelles
multiply in numbers and new viruses are formed. The host cell’s DNA is then deactivated and
the host cell bursts (lysis) releasing with it the new bacteriophages these will then go on to
attack the surrounding bacteria and the cycle repeats itself. If it is possible to introduce Phages
into the human body they can attack the disease causing bacteria(pathogens) and so, can be
used as an alternative to antibiotics.

HOW CAN WE USE BACTEROPHAGES AS AN ALTERNATIVE TO ANTIBIOTICS?
In a 1938 clinical trial, 219 patients with Dysentery (a bacterial intestinal disease which is often
caused by consumption of dirty water. A common symptom associated with Dysentery is the
presence of blood in the stool) were treated solely with a Phage cocktail consisting of phages
which target a range of different bacterial infections such as E. coli and salmonella this phage
cocktail was administered both orally and rectally. After a day 28% of patients suffering with
blood in their stool were relieved of this symptom. Furthermore, in Poland physicians have had
a 90% success rate using phages against MRSA. These results are promising and it is important
to remember that the results shown are from the 1900s and with ever growing advances in
technology phages could very well have a much higher success rate today.
Bacteriophage v antibiotics
Bacteriophages Antibiotics
Specificity Specificity
- As I have previously mentioned - Antibiotics, particularly broad-
bacteriophages are specifically spectrum antibiotics target a range of
targeted at one or similar bacteria bacteria in the body including the
strands. This means that useful bacteria in the gut which are
bacteriophages will only kill disease needed to create vitamins and
causing bacteria and will not kill the minerals. This is a major
“useful” bacteria in our gut which is disadvantage to antibiotics
used to make vitamins. This is a
major advantage to the use of
bacteriophages as antibiotics.

 Resistance Resistance
- Like Bacteria, phages also have the - resistance among antibiotics is
ability to mutate and evolve. So as becoming an increasingly prominent
the bacteria evolve the phases evolve issue. Unlike phages antibiotics do
in step with the antibiotics so not have the ability to evolve and
resistance is less of a problem with form mutations and so they cannot
phages. If it does so happen that the evolve along with the bacteria
bacteria evolve so great such that meaning they bacteria are left to
they form a resistance to bacteria, thrive. The US death by Antimicrobial
there is an abundance of different resistance (AMR) was more than
bacteriophages to available to attack 23,000 in the US alone.
the new resistant strands.
Furthermore, in order for bacteria to
become resistant to Phages they
must give up their resistance to
antibiotics.

Knowledge Knowledge
- due to a lack of human experiments, - antibiotics have been widely used
many governmental bodies have not since the late 1900s and are widely
approved the use of Phages for available in most developed
medical use on bacterial infections. countries. They are taken by millions
There are also no regulatory across the globe daily and there is an
guidelines on the Production, quality abundance of literature and
and safety of them. The HPRA knowledge about their use and
(Health Products Regulatory adverse effects. This is an advantage
Authority) in Ireland has not to antibiotics. Some people do not
approved the use of them in a clinical believe antibiotic resistance is as big
setting nor has the EMA (European of a problem as scientists believe.
medications agency) or the FDA They believe in the Wise
(federal Drug Administration) In the Management of antibiotics. This is
US. This is a major disadvantage to discussed in greater detail in the
antibiotics which could massively “conclusion” method
hinder their possible use.


THE BEST OF BOTH WORLDS?
One of the best possible methods to prevent antibiotic resistance is the combination of
bacteriophages and antibiotics. When bacteriophages attack a bacterial cell the bacterial cell
will attempt to form resistance against the bacteria. However, in order for bacteria to form a
mutation against bacteriophages they must first give up their resistance to antibiotics. If could
introduce both antibiotics and bacteriophages the phage’s would make the antibiotics give up
their resistance and then the antibiotics would be introduced to kill the bacterial cell. This has
already been tested on a patient in the US who had pseudomonas aeruginosa (PA) which is
resistant to most antibiotics. He was given a phage-antibiotic mixture into his chest cavity.
Within a week he was completely cured of PA.
THE DOWNFALL OF BACTERIOPHAGES
The phenomenon of using bacteriophages to replace antibiotics is not a new one and has been
investigated since the 1960s. The first hurdle to overcome is the specificity of antibiotics. This is
useful in relation to the fact that they do not kill our precious gut bacteria. However, this
specificity means that we must collect thousands of different phages to treat infections. This is
an even larger problem for infections that are a result of a number of different bacteria where
dozens of different bacteriophages are needed to treat the infection whereas only one or two
broad-spectrum antibiotics could be used. A Second hurdle is the risk that bacteriophages are
recognised as a foreign body by our immune system and so trigger an immune response. For
this reason It may not be possible for them to be used a second time on a patient. Another
hurdle is sheer price associated with creating “phage cocktails”, a mixture of different
bacteriophages to treat infections.

METHOD TWO: THE USE OF SYNTHETIC MOLECULES
While most of the research focuses on the use of living organisms that produce antibodies and
looking back at the original research that Flemming conducted to discover antibiotics.
Companies like IBM are focusing on making manmade synthetic molecules as a last line of
defence against superbugs



IBMs RESEARCH
IBM have created what they call a “guanidinium- functionalized polycarbonates”. These
polycarbonates have a unique method to kill
bacteria. The polymer (a polymer is essentially
a long repeating chain of connected molecules
e.g.: the plastic in a bin bag) carries a negative
charge and the peptinoglycan bilayer of the
bacteria contains a positive charge. This means
that the positively charged polymer is attracted
to the negatively charged bacteria surfaces
(almost like a magnet) it then bursts through
the membrane and turns the cell contents solid
killing it. It does this so quickly that the bacteria
do not have time to mutate.




ADVANTAGTES TO IBMs POLYMER
Our main concern with the use of any alternative to antibiotics is whether or not bacteria can
form a resistance to them. In IBMs Research blog they state that “They found that the bacteria
did not show any resistance development even after multiple treatments with the polymer” this
is a major advantage to the use of the polymer. This also seems to trump over bacteriophages
to which bacteria can still develop resistance to antibiotics.

As I have mentioned the polymer attaches on to the bacteria electrostatically meaning even if
the bacteria undergo changes to its internal make-up (e.g.: mutations) the polymer will still be
able to identify it because even if it evolves its peptidoglycan bilayer will still hold the negative
charge. This trumps antibiotics which will not be able to target bacteria once it evolves.

Another advantage to the polymer is the fact that it is biodegradable. In the past other
synthetic molecules usually killed bacteria in exchange for toxicity to the liver which was tasked
with the job of breaking down the toxic polymer. The polymer essentially comes in, kills the
bacteria and leaves leaving no harmful effects to other human organs it can kill the bacteria in
under three days.

Similar to the bacteriophages, another advantage of the polymer is the specificity of the
polymer. This means it is targeted at specific bacteria and will not cause damage to our
precious intestinal bacteria. Previous synthetic polymers had the difficulty of causing lysis
(bursting of the bacterial cell) to the bacteria in the bloodstream which released toxins which
could be deathly to the patient.



DISSADVANTAGES TO IBMs polymer
IMB have successfully tested the polymer on mice and it has shown results of no toxicity and
they were able to eradicate five of the most prevalent bacterial infections including MRSA and
pseudomonas aeruginosa. However, this is all well in terms of mice but we don’t know if the if
the polymer will be as biodegradable in the human body. The possible accumulation of the
polymer in the body could be very dangerous even deathly.

Secondly, a lab-made polymer could be considerably more expensive than antibiotics. As multi
drug resistant bacteria are still in the minority today there might be a very limited market for
the polymer and it questions whether people will choose it over traditional antibiotics.

However, bacteria are clever and so it is possible they can form a resistance to the polymer.
James Hedrick, a researcher at IBM stated in an interview with Popular science that “These are
really clever bacteria. I am certain that over decades, they will figure out a way to elude the
therapy”

METHOD THREE: IMMUNISATION
Immunisation(vaccination) may not appear as one of the most obvious methods to prevent
antibiotic resistance and that is because they indirectly prevent Antibiotic resistance by
providing vaccinations we can prevent the development of bacterial infections in the first place
which prevents us from using as much antibiotics as we would otherwise do so. It is estimated
that if every child in the world received a vaccination to prevent them from infection with
streptococcus pneumoniae (the strand of bacteria which causes pneumonia, meningitis and
middle ear infections), this would prevent an estimated 11 million days of antibiotic use a year
(WHO,2016)

BENEFITS OF IMMUNISATION AGAINST AMR
The first and most obvious benefit is the way that they prevent the rise of AMR by reducing the
need to use antibiotics in the first place. But they also have more less obvious effects, many
viral infections which cannot be treated with antibiotics have secondary bacterial side effects
which are more than always treated with a long course of antibiotics. This means that vaccines
can prevent both viral and bacterial infections which

There is also an extremely low risk (if any at all) for bacteria to form resistance to vaccines as
vaccines are used in a prophylactic (preventative) manor while antibiotics are administered
after the infection has started vaccines, by contrast prevent resistant bacteria forming in the
first place. Vaccinations against diphtheria and pertussis, for example have been around for 70
years without developing resistance.

Furthermore, vaccines also have an impressive track record for example the influenza vaccine
has saved more than 40,000 lives over a nine-year period.
Immunisation also comes with an added benefit. Its known as herd immunity which is the
simple idea that even if one person is immunised then others are less likely to develop
infections, simply because they are exposed to it less.

DISSADVANTAGES TO IMMUNISATION AGAINST AMR
Immunisation always poses a possible risk of adverse reactions many are mild however, some
can be serious leading to anaphylaxis (the gradual narrowing of the oesophagus). As with the
previous methods I have discussed there is there is a financial disadvantage – vaccinations are
very costly. Another disadvantage is it would be impossible to vaccinate children for every
single possible infection. However, by vaccinating children for the most common infections it
could massively reduce the use of antibiotics.

CONCLUSION
In conclusion, the three methods are all viable methods to reduce antibiotic resistance.
However, the question of which one is the most suitable and feasible still remains.
Bacteriophages are certainty an option. Their specificity reduces the possibility that our
“useful” gut bacteria are killed and their ability to mutate and evolve in step with the bacteria is
a major advantage to prevent resistance to the Phages. The combination of bacteriophages and
antibiotics is also hugely promising as we already know that antibiotics pose no toxicity to the
body. Furthermore, in order for bacteria to become resistant to bacteriophages they must first
give up their resistance to antibiotics these are major advantages to bacteriophages. However,
the possibility of having to find, analyse and distribute each bacteriophage for every type of
bacteria is a major disadvantage particularly for infections made up of a number of different
strands of bacteria.

The use of synthetic molecules is feasible in theory. Results from IBMs polymer look promising.
However, they are still a few years away from human testing and have only tested on lab rats so
far. IBM have proven that their polymer has no toxicity associated with it in lab rats. However,
the human body may have a different reaction and the risk for rejection could be high.

Immunization appears to be one of the most feasible options. Millions of people are inoculated
daily and very few have adverse reactions for example, the risk of having an adverse reaction to
the FLU shot is between 1-2%. It also allows us to use antibiotics as a fall back method rather
than the first line of defense which will reduce antibiotic resistance. however, immunization is
not a complete alternative to antibiotics it merely reduces the need to use antibiotics this may
not be enough to fully prevent antibiotics as more multi-drug resistant bacteria may develop
faster than we think. It is also important to keep in mind that immunization is a long term
solution one which may not be very useful in our generation but could just save the next from
antibiotic resistance.

While all of these novel methods seem very promising in theory. Many are still skeptical about
just how much of an emergency antibiotic resistance really is. Many still believe that the
current methodology by which; bacteria evolve, humans do research and new antibiotics are
formed to kill the resistant bacteria as the others become obsolete is still sustainable. They
believe that methods such as bacteriophages and are far-fetched and unsustainable. They
believe in the simple idea of wise management. By which people are informed about antibiotics
and are urged to finish the course and only take them for the prescribed time. They believe that
doctors must be better informed (particularly in third world countries) about this and the
dangers that come with antibiotics. It is important to take into consideration this other side of
the argument because it is in essence the method which we have been using to prevent AMR
for the past 70 years. Other methods which have not been mentioned in this investigation such
as Anti-microbial peptides and bacteriocins are also being researched. The debate about the
which is the best method will require further study and analysis but one thing is for sure –
bacteria will continue to evolve and form resistance unless we find a solution. Fast.


PERSONAL OPINION:
In my opinion immunisation is the best way method to solve Antibiotic Resistance for the
following reasons:
- We have an immense amount of knowledge about how immunisation works. It is
estimated that 278 million doses of vaccines are given in the US every year
- they can allow antibiotics to become a backup option rather than the primary
treatment for bacterial infections. This means that antibiotics would not have to be
used as much and so it would decrease the risk of resistance.
- the risk for adverse reactions from Vaccines is very low many tolerate vaccines very
well.
 - once the vaccines are created they would be very quick to be brought into the market-
as vaccines are already used in most countries governments would not have to draft
completely new guidelines on their use.
- Quick - it is expected by as early as 2020 we could have vaccines for the major multi-
drug resistant bacteria strands such as staphylococcus aureus and c.difficile.
- Easy – a vaccine administration is very simple and can be performed by registered
nurses other methods like the use of synthetic molecules and bacteriophages would
require long hospitalisation or even surgical administration.
All of these reasons make for an easy integration into the healthcare system. Other
methods like bacteriophages would require long investigations and multiple human trials
which could take up to 10 years before it is commercially viable in countries like Ireland and
the UK. In my opinion, for this method to work we need to encourage the research into
future vaccinations and encourage as many young people as possible to receive vaccines.

REFLECTING ON THE RELIABILITY OF SOURCES
All information in my research investigation has been sourced from scientific reports and PhD
theses from trusted websites like https://www.ncbi.nlm.nih.gov/ which have been simplified
for the purpose of this report. However, during my research study I came across a number of
bias sources. Due to the nature of my study there was an abundance results from
pharmaceutical companies with their intentions being to sell their products the information
was therefore inaccurate, bias and unreliable. In order to uphold the integrity of my
investigation I used search engines such as https://scholar.google.com/ and
https://www.researchgate.net/. I also cross-checked the information with other research
studies and websites in order to insure the most accurate investigation as I possibly could.





































REFRENCES
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MODULE 3 – Rates of adverse vaccine reactions - WHO Vaccine Safety Basicsvaccine-safety-
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Request PDFwww.researchgate.net
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Industrywww.ncbi.nlm.nih.gov
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Department of Health (2017). Ireland’s National Action Plan on Antimicrobial Resistance 2017-
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on-antimicrobial-resistance-2017-2020/
http://news.mit.edu/2017/antibiotic-nanoparticles-fight-drug-resistant-bacteria-0712
https://nyaspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/nyas.12468
https://futurism.com/synthetic-microbe-next-antibiotic

This scientific review may contain images for which is writer of this review is not the copyright
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prior consent. This scientific review has been prepared in accordance with Section 53(5) of the
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recommended citation - Cathal Buckley - “A REVIEW INTO THE POSSIBLE METHODS TO PREVENT THE DEVELOPMENT
OF ANTIBIOTIC RESISTANCE” - 2019