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Trigger 6: Antimicrobial peptides Questions And Detailed Answers
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Trigger 6: Antimicrobial peptides scale - Answer-Physical extension expands 12 orders of magnitude i.e. 10-9 to 1015 and temporal timescales from seconds to years in 10 to the 50 in biological processes. Studying on all this magnitude is very difficult creating challenges in antibiotic resistanc...

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  • April 1, 2024
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  • 2023/2024
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Trigger 6: Antimicrobial peptides
scale - Answer-Physical extension expands 12 orders of magnitude i.e. 10-9 to 1015 and
temporal timescales from seconds to years in 10 to the 50 in biological processes. Studying on
all this magnitude is very difficult creating challenges in antibiotic resistance

complexity of biological membranes - Answer-Typical eukaryotic cell has lots of organelles such
as nucleus, mitochondria, lysosomes, internal systems and flagella. Biological membranes for
example and membrane systems which can make up 1/3 weight of a cell. Fluid bilayer structure
which spontaneously assemble in water due lipids which are amphilic so hydrophobic head to
hydrophilic tail and usually are highly impermeable. These means have membrane proteins
such as large toxins, also channels and peptides creating challenges in antibiotic resistance

The rise of antibiotics - Answer-came in 1930's with penicillin in 1928 and along with
improvements with hygiene, public health campaigns and invention of sewers deaths due to
infectious diseases have improved. Real take on in 1950's and 1960 post WW2 development of
all antibiotics. However in last 30 years no new family of antibiotics has been development
named discovery void.
Usage has increased particularly in upper middle income and lower income countries due their
provided massive increase in life expectancy. High income countries like UK has not really
changed however there is poor compliance resulting in antimicrobial resistance where course
are not being finished . That main usage increase is in livestock as has commercial value and
this is big cause for antimicrobial infections. In USA 1/100 people approx have bacterial
infections caused by resistant bacteria per year and it has resulted in 35,900 deaths. Expected
to cause 15 million deaths by 2050. Causes setbacks in many modern medicine developments
such as chemotherapy and organ transplant as practice becomes more dangerous without
antibiotics.

Antibiotic development crisis - Answer-Number of new antibiotics approvals is declining
(CDC / FDA data) 42 new antibiotics in clinical development (June 2019)
Economic drivers:
Cost of drug development
Poor returns (emergency drugs)
Life-style drugs more profitable. 42 antibiotics new in clinical development which is negligible
compared to other disease types despite being one of biggest threats to man kind and biggest
cause of death in future. This low amount of development is because that high cost of drugs
especially tasking into account all that drugs that fail for that ones for work, e.g. approx 4-11
billion dollars. Poor return were antibiotics are not being used enough to compensate cost.
Therefore lifestyle drugs more favourable cost for company.

Drug Development Process - Answer-The evaluation of pharmaceuticals and
biopharmaceuticals is a highly regulated process requiring many steps to prove a drug is safe
and effective. Takes around 12 years

Antibiotic targets - Answer-Bacterial cell wall by B-lactam and Vancomycin, DNA/RNA synthesis
of fluoroquinolones and rifamycins, Folate synthesis of trimethoprim and sulfonamides and cell
membrane of daptomycin, protein synthesis of tetracyclines, macrolides aminoglycosides,

, causes of antibiotic resistance - Answer-Over prescription or inappropriate prescription of
antibiotics, patients not finishing entire antibiotic courses, overuse of antibiotics in livestock and
farming, poor infection control in healthcare, availability of new antibiotics. Antibiotics tend to
have a single mechanism of action which makes it easy foe bacteria to develop mechanisms to
resist them

biological mechanism of how antibiotic resistance - Answer-1. Genetic mutation occurs (usually
in the plasmid DNA) 2. Causes the transcription of a protein that aids in the resistance to
antibiotics 3. This bacterium survives the antibiotic treatment and divides 4. This produces a
colony of bacteria resistant to the antibiotic

Mechanism of resistance - Answer-ntimicrobial inactivation: specific enzymes which can break
down or inactivate antibiotics e.g. beta-lactam ring hydrolysed the beta-lactamases. Cell wall
alterations: mutated cell wall and drug binding sites e.g. penicillin binding protein 2a in S.aureus
has lower affinity to beta lactams allowing survival in greater concentrations. Persistence:
formation of biofilms. Porin alterations: porin mutation alter the size and shape to prevent
antibiotics from entering, proin loss reduces antibiotic entry points, efflux pumps specific pumps
which remove intracellular antibiotics. e.g. streptococcus

Biofilms - Answer-in response to environmental stress communities of slime-secreting bacteria,
cell adhere to each other and clump together which makes it physical barrier preventing
antibiotics from acting on bacteria, enables large colonies to for with lots of potential antibiotic
resistant mutations

Membrane-active antimicrobial peptides (AMPs) discovery - Answer-Peptides are good drugs
as large molecules meaning very specific for target and reduce AE compared to small
molecules.
Membrane-active AMPs are found in many organisms (1) and typically exist as 15-20 long
amino acids (2).
Initially they were recognised for other functions, but they have since been shown to possess
great antimicrobial activity (3) and are a potential source for new antibiotics against multi-
resistant pathogens (1).
E.g.., Lactoferrin protein à Initially it was was recognized for its ability to bind to iron but later
studies demonstrated that it was able to kill bacteria via an iron-independent mechanisms of
membrane disruption. This is typical of AMPs (3)
They have also been found in the innate immune systems of many organisms, defending the
host against invading bacteria (2).Antimicrobial peptides are very easy to synthesize in a few
days and can be made very cheaply. Fill that gap of future antibiotic drug design has can modify
very easily 15aa to match bacteria. Chemical reptoir of peptides in limitless as many aa.AMPS
were first discovered in 1980 being found in haemolymph, mammalian neutrophil granules and
frog skin secretions. Since then over 200 AMPS have been discovered. Firstly recognised for
clinical use in 1939 when antimicrobial states were isolated form bacillus brevis and were found
to exhibit activity both in vitro and in vivo in a wide range of gram positive bacteria.

Issues with designing AMPS de novo - Answer-from scratch : in all forms of life there are 20aa,
typical AMP is 15 aa, this therefore means there are unlimited (20 to the power of 15)
combinations of possible AMP's. Therefore it is not possible to make all these peptides and try
them out. Need a method to narrow down functional and effective AMPS and this is where
computational techniques come in.

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