antibiotic resistance.pptx

The history of antibiotics
Antibiotics or antibacterials are a type of antimicrobial used in the treatment
and prevention of bacterial infection. They may either kill or inhibit the growth of bacteria.
Several antibiotics are also effective against fungi and protozoans, and some are toxic to
humans and animals, even when given in therapeutic dosage.
350-550 AD traces of tetracycline have been found
in human skeletal remains from ancient Sudanese
Nubia (Armelagos, 1980). Source of the antibiotic =
the Nubian beer. The grain used to make the
fermented gruel contained the soil bacteria
streptomyces, which produces tetracycline.
The ancient Egyptians and Jordanians used beer to
treat gum disease and other ailments.
In traditional Chinese medicine a paste from
chewed barley and mouldy apple was made and
put on the surface of wounds.
In the Jewish Talmud a therapeutic is mentioned
that consist of mouldy corn soaked in water or date
wine.

In 1640 John Parkington, London
apothecary and King‘s herbalist advises
that moulds have a curative effect when
applied to infections.
In 1870, Sir John Scott Burdon-Sanderson observed that
culture fluid covered with mould did not produce bacteria.
1877 Louis Pasteur observed that cultures of the anthrax
bacilli, when contaminated with moulds, became inhibited -
bacteria kill other bacteria.
1897, Ernest Duchesne healed infected guinea pigs
from typhoid using mould (Penicillium glaucium);
doctorate thesis ‘Contribution to the study of vital
competition in micro-organisms: antagonism between
moulds and microbes’.

In 1893 Bartolomeo Gosio (1863-1944) is able to isolate
Mycophenolic acid out of moulds from the genus penicillium
and showed that it was able to inhibit the grow of bacillus
anthracis. His work never found international recognition
probably because it was written in Italian and not translated.
“When I woke up just after dawn on September 28, 1928, I
certainly didn't plan to revolutionise all medicine by
discovering the world's first antibiotic, or bacteria killer. But I
suppose that was exactly what I did.”
Fleming was born on 6 August 1881 at Lochfield farm, Scotland
as the third of the four children. In 1903 he enrolled at St
Mary's Hospital Medical School and qualified with an bachelor
degree from the school with distinction in 1906. He became
assistant bacteriologist to Sir Almroth Wright, a pioneer in
vaccine therapy and immunology.
1928, Sir Alexander Fleming
In 1909 Paul Ehrlich discovered arsphenamine, the first
synthetic antibiotic as a treatment for syphilis.

In 1928, while working on influenza virus, he observed that mould had developed
accidently on a staphylococcus culture plate and that the mould had created a bacteria-free
circle around itself. He was inspired to further experiment and he found that a mould
culture of Penicillium fungi prevented growth of staphylococci, even when diluted 800
times.
1928, Sir Alexander Fleming
In 1939 Ernst Chain began, with Sir Howard Florey, a
systematic study of antibacterial substances produced
by micro-organisms. This led to his best known work,
the reinvestigation of penicillin and to the discovery of
its chemotherapeutic action.
Fleming, Florey and Chain jointly received the Nobel
Prize in Medicine in 1945.
In 1943, Selman Waksman discovered that soil Streptomyces produce
antibiotics. Nobel prize in 1952 for discovery of Streptomycin.
He discovered over twenty antibiotics (a word which he coined) and
introduced procedures that have led to the development of many
others.

Penicillin production in the beginning:
glass flasks and milk churns used for making early forms of penicillin
The United States to produce 2.3 million doses in time for the invasion of
Normandy in the spring of 1944.

The production of antibiotics
With advances in medicinal chemistry, most modern antibacterials
are semisynthetic modifications of various natural compounds.
Semisynthetic : beta-lactam antibiotics. Penicillins -produced by fungi in the
genus Penicillium- and cephalosporins vs bacterial infections caused
by staphylococci and streptococci. Carbapenems - one of the antibiotics of last resort for
many bacterial infections, such as Escherichia coli and Klebsiella pneumoniae. (developed
from the carbapenem thienamycin, a naturally derived product of Streptomyces cattleya).
Natural : aminoglycosides. Aminoglycoside
antibiotics display bactericidal activity against gram-
negative aerobes and some anaerobic bacilli where
resistance has not yet arisen, but generally not
against Gram-positive and anaerobic Gram-negative
bacteria. They include the first-in-class
aminoglycoside antibiotic streptomycin derived from
Streptomyces griseus, the earliest modern agent
used against tuberculosis.

The production of antibiotics
Synthetic: the sulfonamides, the quinolones, and the oxazolidinone.
Sulfamethoxazole: It is commonly used to treat urinary tract
infections. Alternative to amoxicillin-based antibiotics to
treat sinusitis. It can also be used to treat toxoplasmosis and
it is the drug of choice for Pneumocystis pneumonia, which
affects primarily patients with HIV.
Fluoroquinolones are broad-spectrum antibiotics (effective
for both Gram-negative and Gram-positive bacteria) that
play an important role in treatment of serious bacterial
infections, especially hospital-acquired infections and others
in which resistance to older antibacterial classes is
suspected. (i.e. Ciprofloxacin).
Some of the most important oxazolidinones are the last generation of antibiotics used
against gram-positive pathogens, including superbugs such as methicillin-resistant
Staphylococcus aureus. These antibiotics are considered as a choice of last resort where
every other antibiotic therapy has failed (i.e. Tedizolid).

The Ideal Drug
Selective toxicity: against target pathogen but not against host -greater harm to microbes than
host, done by interfering with essential biological processes common in bacteria but not
human cells.
There is no perfect drug.
Bactericidal vs. bacteriostatic
The level of anti-microbial activity that kills an organism (99.9% death of test organism -
Minimal Bactericidal Concentration; MBC)
The level of anti-microbial activity that inhibits the growth of an organism (Minimal
Inhibitory Concentration; MIC)
Favorable pharmacokinetics: reach target site in body with effective concentration -
drug interns, how drug is distributed, metabolized and excreted in body.
Spectrum of activity: broad vs. narrow.
Lack of “side effects”- effective to toxic dose ratio
Therapeutic index: the lowest dose toxic to the patient divided by the dose typically used for
therapy.
Little resistance development

Antibiotic Mechanism of Action

ACTION AS ANTI-METABOLITES:
Sulfonamides are structural analogs and competitive antagonists of para-aminobenzoic
acid (PABA). They inhibit normal bacterial utilization of PABA for the synthesis of folic acid,
an important metabolite in DNA synthesis. The effects seen are usually bacteriostatic.
Folic acid is not synthesized in humans, but is instead a dietary requirement. This allows for
the selective toxicity to bacterial cells (or any cell dependent on synthesizing folic acid) over
human cells. Bacterial resistance to sulfonamides is caused by mutations in the enzymes
involved in folic acid synthesis that prevent the drug from binding to it.
INHIBITION OF PROTEIN SYNTHESIS:
The inhibition of protein synthesis is mediated through binding to bacterial ribosome.
Aminoglycoside presence in the cytosol generally perturbs peptide elongation at the 30S
ribosomal subunit, giving rise to inaccurate mRNA translation and so biosynthesis of
proteins that are truncated or that bear altered amino acid compositions at particular
points. Specifically, binding impairs translational proofreading leading to misreading of the
RNA message, premature termination, or both, and so to inaccuracy of
the translated protein product.
Aminoglycosides: bactericidal activity against most gram-negative aerobic and facultative
anaerobic bacilli and most gram-positive bacteria. They require only short contact time, and
are most effective against susceptible bacterial populations that are rapidly multiplying

INHIBITION OF DNA/RNA SYNTHESIS:
Quinolones exert their antibacterial effect by preventing bacterial DNA from unwinding
and duplicating.
INHIBITION OF CELL WALL SYNTHESIS:
Bacteria constantly remodel their peptidoglycan* cell walls,
simultaneously building and breaking down portions of the
cell wall as they grow and divide.
β-Lactam antibiotics inhibit the formation of
peptidoglycan cross-links in the bacterial cell wall; this is
achieved through binding of the β-lactam ring of penicillin
to the enzyme DD-transpeptidase. As a consequence, DD-
transpeptidase cannot catalyse the formation of these
cross-links, and an imbalance between cell wall production
and degradation develops, causing the cell to rapidly die.
(β-lactam ring has structural similarity with normal
substrate for the enzyme).
Some bacteria make beta lactamase, an enzyme that breaks
down the ring structure and thus inactivates penicillins.
*polymer consisting of sugars and amino acids

13
Antibiotic Resistance
Antimicrobial resistance (AMR) is when microbes are resistant to one or
more antimicrobial agents,used to treat infection.
Microbes which are resistant to multiple antimicrobials are termed multidrug
resistant (MDR) (or, sometimes in the lay press, superbugs).
Antimicrobial resistance is a growing problem in the world, and causes millions of deaths
every year.
As resistance to antibiotics becomes more common, a greater need for alternative
treatments arises. Despite a call for new antibiotic therapies, there has been a continued
decline in the number of newly approved drugs.
http://antibiotic-action.com/

14
Antibiotic resistance poses a grave and growing global problem: a World Health
Organization report released April 2023 stated, "this serious threat is no longer a
prediction for the future, it is happening right now in every region of the world and has
the potential to affect anyone, of any age, in any country. Antibiotic resistance—when
bacteria change so antibiotics no longer work in people who need them to treat
infections—is now a major threat to public health."

15
Clinical deployment of new antibiotics (blue bars) has quickly been followed by the
evolution of bacteria able to resist their effects (red). During the golden age of discovery,
150 types of antibiotics were developed. Since then, the spread of resistance has greatly
outpaced the rate of drug development. The Infectious Disease Society of America
estimates that 70% of hospital-acquired infections in the United States are now resistant
to one or more antibiotics.

16
Antibiotic resistance can
be acquired in two basic
ways. In vertical
transmission, a
bacterium accumulates
errors or mutations in its
genome during
replication; some of
those changes (red) give
the ability to resist
antibiotics and are
passed on to subsequent
generations. In
horizontal transmission,
resistant genes are
swapped from one
microbe to another.
This can occur via three mechanisms: transformation, when bacteria scavenge resistance
genes from dead bacterial cells and integrate them into their own genomes; transduction,
when resistance genes are transferred by bacteriophages (viruses that infect bacteria); or
conjugation, when genes are transferred between bacterial cells through tubes called pilli.

17
Four mechanisms of resistance:
impermeable barrier (a) blocks
antibiotics (blue spheres) because
the bacterial cell membrane is now
impermeable to the drug.
Target modification (b) alters the
proteins inhibited by the antibiotic,
so the drug cannot bind properly.
Antibiotic modification (c) produces
an enzyme that inactivates the
antibiotic.
Efflux (d) employs genes coding for
enzymes that actively pump the
antibiotic out of the cell.
Understanding factors that
influence resistome evolution and
dissemination may both extend the
life of current drugs and point
toward new diseasefighting
strategies.

18
The four main mechanisms by which microorganisms exhibit resistance to antimicrobials
are:
Drug inactivation or modification: enzymatic deactivation of penicillin G in some
penicillin-resistant bacteria through the production of β-lactamases, enzymes that breaks
down the ring structure and thus inactivates penicillins.

19
Alteration of target site: for example, alteration of PBP (Penicillins Binding Proteins)
in penicillin-resistant bacteria.
Alteration of metabolic pathway: for example, some sulfonamide-resistant bacteria do
not require para-aminobenzoic acid (PABA), an important precursor for the synthesis
of folic acid and nucleic acids in bacteria inhibited by sulfonamides, instead, like
mammalian cells, they turn to using preformed folic acid.
Reduced drug accumulation: by decreasing drug permeability or increasing
active efflux (pumping out) of the drugs across the cell surface.. These efflux pumps are
often activated by a specific substrate associated with an antibiotic. Some types
of efflux pumps can act to decrease intracellular fluoroquinolone concentration.
Beta-lactam antibiotics
permanently inactivate PBP
enzymes, which are essential
for bacterial life, by
permanently binding to their
active sites. MRSA (Methicillin
resistant Staphylococcus
aureus), however, expresses a
PBP that does not allow the
antibiotic into its active site.

20
MEDIATIONS OF Antibiotic Resistance
Interconnections between people, animals, and the environment make it easy for
antibiotic resistant bacteria to jump from one species to another.
For instance, a resistant strain living in soil could travel through runoff and get passed on
to humans via drinking water or recreational swimming.
Multiple routes of exchange propel the evolution and spread of resistance.

21
Some bacteria with resistance to antibiotics predate the medical use of antibiotics by
humans; however, widespread antibiotic use has caused more bacteria to become
resistant, a process called evolutionary pressure.
• Antibiotic increasing global availability
over time since the 1950s
• Their uncontrolled sale resulting in
antibiotics being used when not indicated.
• Prescribing or obtaining broad-spectrum
antibiotics when not indicated: these are
more likely to induce resistance than
narrow-spectrum antibiotics.
• Antibiotic use in livestock feed at low doses
for growth promotion is an accepted
practice in industrialized countries which
leads to resistance.
• Releasing large quantities of antibiotics
into the environment during
pharmaceutical manufacturing.

22
World Health Organization recommendations
An April 30, 2014, report by the WHO addressed this issue, and a summary was described in
a WHO press release as follows:
People can help tackle resistance by:
using antibiotics only when prescribed by a doctor;
completing the full prescription, even if they feel better;
never sharing antibiotics with others or using leftover prescriptions.
Health workers and pharmacists can help tackle resistance by:
enhancing infection prevention and control;
only prescribing and dispensing antibiotics when they are truly needed;
prescribing and dispensing the right antibiotic(s) to treat the illness.
Policymakers can help tackle resistance by:
strengthening resistance tracking and laboratory capacity;
regulating and promoting appropriate use of medicines.
Policymakers and industry can help tackle resistance by:
fostering innovation and research and development of new tools;
promoting cooperation and information sharing among all stakeholders.

23
Discovery of teixobactin = a new class of antibiotics, the first to be described in many years.
The authors showed that teixobactin was able to kill bacteria that cause wound infections
from cuts and scratches such as Staphylococcus aureus including MRSA, those that cause
pneumonia (Streptococcus pneumoniae) and Mycobacterium tuberculosis (TB).
Teixobactin was also effective in curing experimental infections of MRSA in mice.
However, for teixobactin to become a drug to treat infections in people, clinical trials will
need to be carried out to make sure that the drug is safe and works in patients. To do this,
first it will need to be formulated so that the antibiotic remains active when inside the
human body.
Even if teixobactin itself cannot be turned into a new drug, it could well be the first of a
series of new drugs in its class.

24
Teixobactin works differently to other antibiotics currently used to treat bacterial infections
in people (and animals).
No teixobactin-resistant Staphylococcus aureus were found under a variety of conditions,
leading the authors to suggest that it will be difficult for bacteria that cause infections in
people to become resistant to teixobactin.
Teixobactin comes from a microbe that lives in the soil.
Often the microbe that produces the antibiotic, and sometimes its close microbe
neighbours, are resistant to the antibiotic.
Occasionally, these natural antibiotic resistance genes have found their way into bacteria
that cause infections in people. This is the most likely route of any resistance to teixobactin.
However, this could be a very rare occurrence because the bacterial strains that cause
infection in people would need to have mixed with the teixobactin-resistant soil bacteria.
It is likely that any new drugs would be used much more carefully so that the emergence of
resistance is minimised.

25
According to the World Health Organization’s report in April 2014, one of the major
concerns of doctors around the world is antibiotic resistance in bacteria that
microbiologists call Gram-negative bacteria such as E. coli and Klebsiella.
These bacteria are different to MRSA and have a very different cell structure which makes it
very hard to get antibiotics into Gram negative bacteria and once inside many antibiotics
are pumped out.

antibiotic resistance.pptx

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