Biology Depth Study
Analyze the antibiotic resistance crisis and how
research into phages could solve it.
Kevin Ryan
Table of Content
●
●
●
●
●
Abstract
○ Outcomes
○ Background
○ Aim
○ Rationale
Introduction
Body
○ 1. Antibiotics
■ 1.1 Overuse & Misuse
■ 1.2 Use in livestock
■ 1.3 Overuse
○ 2. Bacteria
■ 2.1 Evidence of bacterial evolution
■ 1.2 Bacteria Evolution
■ 1.3 Superbugs
○ 3. Bacteriophage
■ 3.1 Mechanics
■ 3.2 Phage Therapy
■ 3.3 Phage resistance
■ 3.4 Future for phages
Conclusion
References
Term 2
07/2019
Biology Depth Study
Analyze the antibiotic resistance crisis and how research into phages could solve it
07/2019
Abstract
Outcomes
-
Outcome 11-4
Outcome 11-5
Bio 11-10
Background
This question has been discussed many times in several articles and presentations as it is a relevant issue
Aim
To find out what the antibiotic resistance problem is and if further study into phages could help with it
Rationale
My reasoning for choosing this area of study is the interesting aspects of superbugs but also gain an
understanding of a potential pandemic.
Introduction
Before the 1900s, just a cut was enough to kill a person due
to bacterial infections.. Then in 1928 when Alexander
Flemming discovered penicillin, it had changed the game for
human survival meaning humanity no longer had to live in
constant fear of bacteria. Then the use of antibiotics had
become so prevalent that the value of them and concerns over
bacteria have significantly diminished. This resulted in much
overprescription and excessive use in unnecessary scenarios
such as against the cold. This and other factors has contributed
to bacteria evolving against most antibiotics making
pathogenic bacteria a threatening presence once again This
has become more problematic in recent years as development
of antibiotics has drastically gone down whilst bacterial
resistance has only gone up. Phages which have been the
natural enemy to bacteria since early life has re-emerged in
the spotlight in our post antibiotic era due to their ability to
combat these multidrug resistant pathogens
.1. Antibiotics
Antibiotics which mean anti-life are a category of
antimicrobials that are used against bacteria. They do this by
either preventing, reproduction or killing the bacteria. Beta lactam antibiotics such as penicillin prevent bacteria from
building their peptidoglycan layer which is an important part
as is provides structural support. This leads to immense
pressure causing the bacteria to burst. So bacteria evolve
against this such as having beta- lactamase enzymes which
break beta lactam antibiotics.(9) This is an example of our
biological war against bacteria but recently we have been
losing due to overuse and underdevelopment of antibiotics
Figure 1
Figure 1 which is similar to other graphs and is from a credible
source, visualizes the dropping rate in discovery of new
antibiotics through a graph. This graph shows that in 1983 1987 16 FDA approved antibiotics were discovered but every
decade since has shown decline in discovery with 2002-2012
Biology Depth Study
Analyze the antibiotic resistance crisis and how research into phages could solve it
07/2019
only finding 2. This data is likely a result of antibiotics not
being economically profitable and is one of the major factors
in the antibiotic crisis.
1.1 Overuse & Misuse
Humanity careless use of antibiotics has been a major factor
in the development of resistant bacteria. According to the
CDC(well known disease agency) , ⅓ of antibiotic use is
unnecessary which provide insight on why bacteria have
evolved so fast. Also a substantial amount of antibiotic use is
wasted on viral infections which only hurts peoples
recovery.(10). Hospitals also cause a lot of bacteria evolution
for example when they commonly use broad spectrum
antibiotics.
1.2 Use in livestock
Whilst hospitals are known to be breeding grounds for these
resistant pathogens. is it primarily the agriculture industry use
of antibiotics which has created the largest amount of resistant
strains.
Figure 3 displays the severity of antibiotic crisis with
resistances against common antibiotics such as tetracycline
rising by 30% or penicillin increasing by 15% . It also shows
while still fluctuating,, how bacteria has increased in
resistance over a decade to all 6 antibiotics shown in figure 3.
Figure 4 shows how resistance to Vancomycin increased in us
hospitals overtime which shares a common trend with figure
3 that resistance to bacteria is rapidly increasing over time
with no signs of a meaningful decline
.2. Bacteria
Bacteria are single celled prokaryotes that are found almost
everywhere. The majority of bacteria species can be
considered harmless or even beneficial while the rest are
harmful towards humans. These bad ones are called
pathogenic bacteria and have the ability to cause illness or kill
millions of lives.
2.1 Evidence of bacteria evolution
Figure 2
Figure 2 from the internationally credible source of the UN
shows that 70% of antibiotic use is on animals which tells that
the main reason for the antibiotic resistance crisis is use in
livestock. To make matters worse often these resistant bacteria
created in the animals are then eaten by humans, which is how
it spreads so fast.
The reason antibiotics are used so much in agriculture is
since livestock is often farmed in cheap cramped spaces, it
commonly faces diseases. An example of this, is the once “last
resort” antibiotic, coliston has shown to be countered in
chinese pig farms with the rapid spread of MCR-R Colistin
resistance.(11)
Figur
Bacteria currently are evolving against antibiotics at an
alarming rate. Their evolution matches with charles darwin's
theory of evolution since their exists more bacteria that can
survive to reproduce. In the population of bacteria there exist
natural variation or mutations which allow some to survive
selective pressures or in this case antibiotics. Then the
resistant bacteria is able to reproduce causing the following
generations to consist mostly of the favourable gene. This is
shown in figure 5
1.3 Common antibiotics
This experiment which is reliable because it was done at a
top university, Harvard Medical School, shows a
60cmx40cm petri dish containing increasing amounts of
antibiotics as shown in figure 6. Then e coli is shown able to
mutate and pass through the increasing antibiotic levels and
make it through the middle in just 11 days. This is useful to
Biology Depth Study
Analyze the antibiotic resistance crisis and how research into phages could solve it
07/2019
understanding how a bacteria population have the ability to
evolve in order to make it through the levels visualized by
the different colours in figure 7.(12) Also it reaching the
middle in 11 days is also useful in understanding how the
antibiotic resistance issue is able to spread dangerously fast.
Bacteria
Resistance
Threat level
Acinetobacter
baumannii
●
carbapenem
Critical
Pseudomonas
aeruginosa
●
carbapenem
Critical
Enterobacteriaceae
●
●
carbapenem
3rd generation
cephalosporin
Critical
Enterococcus faecium
●
vancomycin
High
Staphylococcus
aureus
●
High
●
methicillinresistant
vancomycin
Helicobacter pylori
●
clarithromycin
High
Campylobacter
●
fluoroquinolone
High
In addition to bacteria naturally mutating, they have the ability
to spread their immunity in a process called conjugation were
they can exchange plasmids containing their resistant genes.
Then in a process called transformation bacteria are able
harvest dead bacteria for dna allowing them to become more
resistant. These two additional methods of spreading
immunity is why antibiotic resistant is such a problem
Salmonella
●
fluoroquinolone
High
Neisseria
gonorrhoeae
●
Hgih
●
3rd generation
cephalosporin
fluoroquinolone
Streptococcus
pneumoniae
●
penicillin
Medium
2.3 SuperBugs
Haemophilus
influenzae
●
ampicillin
Medium
While bacteria developing resistance to antibiotics is a
growing concern, it is really the Multi drug resistant
organisms (MDRO) that are responsible for the most deaths
since they are resistant to multiple antibiotics.
Shigella spp
●
fluoroquinolone
Medium
2.2 Bacterial Evolution
Bacteria have shown to evolve to protect themselves and
have been doing it to a majority of antibiotics.Ways bacteria
are able to this include moving or replacing the antibiotic
targets This is shown in some Staphylococcus aureus strains
which replaces the gene that beta lactams usually bind to
allowing them to make their cell wall interrupted (13).It also
include bacteria having impermeable or no cell walls which
render most beta lactam antibiotics useless such as penicillin,
oxacillin and methicillin. Other ways involve killing them
with enzymes or just pumping them out(14)
Figure 9(15)
Figure 9 provides supports the theory that superbugs are the
largest threat in the antibiotic crisis as shown in the table
being resistant to our most powerful antibiotics.
Fig
Figure 11
Superbugs are currently responsible for 700,000 deaths
annually and is expected to rise to 10,000,000 by 2050 ,
making it more deadlier than cancer as shown in figure 8
Biology Depth Study
Analyze the antibiotic resistance crisis and how research into phages could solve it
07/2019
Figure 12
The large increase of gonneraoh resistance to cipro in figure
10 reveals the rapidly evolving nature of gonorrhea. Then in
figure 11 it shows how over a couple years there has been a
significant increase in gonnaroeh related cases. These two
data sets suggest how gonneroah is turning into a dangerous
threat by both becoming more resistant and infecting more
people. This trend of superbugs becoming powerful if further
emphasised by Figure 12 which shows the rapid increase in
resistance from the bacteria MRSA, VRE and FQRP. The
similar trends in Figures 10,11,12 all reveal how superbugs
are evolving dangerously fast and becoming one of
humanity’s largest threats.
3. Bacteriophages
Phages are the most abundant viruses in the world and are
the natural predators to bacteria & archaea. These phages
while discovered before antibiotics have always been in their
shadow until recently. The reason for this, is that on numerous
occasions they have shown success in treatment where
antibiotics have not. The lack of research on phages is likely
due to the anti soviet politics and the difficulty to get FDA
approval but once these hurdles are overcome, phages could
potentially be the solution to our current antibiotic resistant
crisis.
3.1 Bacteriophages mechanics
Phages are highly specialized killers that exclusively
attack bacteria. Due to their receptors on their protein
tail only fitting specific cell surfaces, they only attack the
bacteria the are designed against. This already gives
them an advantage over antibiotics since antibiotics
attack both good and bad bacteria while phages are
more specialized. Then they inject their DNA into
bacteria causing it to manufacture phages. Then the
new phages releases endolysin causing the bacteria to
burst, releasing the phages allowing the cycle to
repeat.(16) This approach of killing allows phages to
destroy bacteria regardless of their antibiotic immunity.
3.2 Phage Therapy
Phage therapy is a form of medical treatment is still
in its early trial stages. It involves either administering
the phages orally through tablets or liquid, topically
through cream, directly on wound via bandages or
injected. Generally very limited dosage is required due
to the phages ability to replicate themselves which is a
major benefit over antibiotics. Many success stories of
phages working where antibiotics didn't exist. An
example of this is a man called tom patterson had
caught Acinetobacter baumannii which is bacteria that
is resistant to many antibiotics was about to die but
then after receiving a random cocktail of phages had
fully recovered.(17) Isabelle Holdaway is another
example of phages working with her nearly dying to
Mycobacterium abscessus but after receiving phages
had made a recovery.(20) Both these examples prove
that phages are the solution when there's no hope
against the superbugs. Currently the main
disadvantages with phage therapy so far is the
unknown dosage required, how long it takes to work or
which phages match which bacteria but all of theses
factors could be solved with more research which is
why further study into phages is critical for the fight
against the antibiotic resistant crisis.
3.3 Phage resistance
Phage treatment on bacteria is shown to have another
unintended beneficial effect of making bacteria more
sensitive to antibiotics. While bacteria has recently been
rapidly evolving against antibiotics, it has been fighting
phages for millions of years meaning it has also defense
against phages such absorption blocking,denying entry and
CRISPR mechanism but recent studies suggest that these
process reverse the bacteria's resistance to antibiotics.(18)
Figure 13
In an experiment called Reversal of Antibiotic Resistance by Phage
Resistant Pseudomonas aeruginosa PA01, a sample of Pseudomonas
Aeruginosa was exposed to bacteriophage φs1 causing it to
change from green to brown as shown in figure 14 and had
Biology Depth Study
Analyze the antibiotic resistance crisis and how research into phages could solve it
07/2019
developed phage resistant mechanisms. This phage resistant
strain (prPA01) was shown to lose resistances against
antibiotics, ERT, NRF, KAN, GEN, GAT, IMP. This strain also
had lost 90% of its biofilm making ability making it more
vulnerable to imipenem(IMP). This suggests that a dual use
of antibiotics and phages could be very successful.
engineering technology available, synthetic phages are a
possibility. By developing synthetic phages it will allow us to
overcome the limitations of natural phages such as phage
resistance in bacteria or even choose the bacterial
specialization of the phage.(21) This is why further research
into phages is important
Conclusion
The antibiotic resistance crisis is very real and
approaching us at scary rates. Our man made
pandemic caused by our overuse of antibiotics will
lead to millions of deaths unless we do something.
Phages seem to fill this role with them showing
success in many cases and even offering new
advantages but since these phages have been
neglected they need to catch up in research. Also with
current studies it suggests that in the future that
phages and antibiotics will share a synergistic
relationship. So phages seem like a likely candidate to
solve this crisis if the proper funding and research is
done
References
Figure 14
[1] “Antibiotic Resistance.” 2018. Who.Int. World Health
Organization: WHO. February 5, 2018.
Another experiment was conducted to test the theory that if
OMKO1 phages could latch onto the OprM part of an efflux
pump(pump that get rid of antibiotics) so that the bacteria
would evolve against the OMKO1 phage but in the process
weaken its efflux pump thus making antibiotics more
effective. As shown in the table in Figure 14 this theory is
confirmed by phage resistant bacteria being more
vulnerable then the phage sensitive bacteria to the 4 tested
antibiotics. The graphs reveal that there was a substantial
increase in phage resistant bacteria vulnerability against
antibiotics.(19) Figure 13 and 14 both reveal how even if
bacteria were to become resistant to phages it would still be
beneficial as they would be more susceptible to antibiotics
once again
3.4 Future of phages
Phages have been neglected for a long time in history but
now with its newfound interest in the scientific community,
research on phages hold many new opportunity that could be
vital for the survival of humanity. With modern genetic
https://www.who.int/news-room/fact-sheets/detail/antibioticresistance.
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Biology Depth Study
Analyze the antibiotic resistance crisis and how research into phages could solve it
07/2019
Selection Restores Antibiotic Sensitivity in MDR Pseudomonas
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[17]
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[18]
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[11]
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[14]
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Biology Depth Study
Analyze the antibiotic resistance crisis and how research into phages could solve it
07/2019