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Antimicrobials and

Antimicrobial Drug Resistance

Figure Reference:
Microbiology with
Diseases by Taxonomy
2013 John Wiley & Sons, Inc. All rights
reserved.

BIOM 1005/1905
Dr. Shivanthi Samarasinghe

Learning outcomes:
Learn about range of antimicrobial
and antibiotics.
Able to discuss the mode of
mechanism of action of antimicrobials.
Able to comment on the
mechanism of resistance.

Antimicrobial drugs:
Antimicrobial drugs: drugs that treat
infections
They are often administered internally.
They exhibit selective toxicity.
They may be highly effective at eliminating
one class of microbes (e.g., bacteria), while
ineffective at eliminating others.
They may be of natural origin or
chemically synthesized.

The History of Antimicrobial


drugs:
Paul Ehrlich discovered the specific arsenic
compound that killed trypanosome parasites and
worked against infection syphilis.

Alexander Fleming in 1928


Observed the bread mold Penicillium inhibiting
S. aureus cultures.

Antibiotic effect of the mold


Penicillium:
Figure 10.1 Microbial diseases by
Taxonomy.

Staphylococcus
aureus
(bacterium)

Penicillium
chrysogenum
(fungus)
Zone where
bacterial growth
is inhibited

Analysing the susceptibility of antibiotics


in clinical microbiology labs:

resistant to the antibiotic;


bacteria grows up to the antibiotic disk.

sensitive to
the antibiotic;
Bacteria
creates
A larger zone
of inhibition.

Disk diffusion test on Isosensitest agar


demonstrating an antibiotic resistant clinical
isolate of Escherichia coli.
Samarasinghe et al, EUSTM, 2014.

Disk Diffusion method;


standard method of
determining the
susceptibility of bacteria.
Bacterial sample is grown
on a special agar media;
effective in diffusing the
chemical.
Zone size is measured to
determine the susceptibility
of bacteria to a specific
antibiotic..

Origins of Antimicrobial drugs:


Natural;
Antimicrobial agents
produced naturally.

Semisynthetic;
Chemically altered
Antibiotics, more effective,
long-lasting, or easier to
administer.

Synthetic;
completely synthesized in
a lab.

Selective toxicity of Antimicrobials


The key to successful chemotherapy requires
selective toxicity (ST);

ST is possible because there are many difference


between the structure and metabolism of the
pathogenic microbe and their hosts.
Antibacterial drugs more common and has largest
diversity compared to other antimicrobial agents.

Fewer drugs (antifungal, antiprotozoal) to treat

Mechanisms of Antimicrobial Drugs


Inhibit ion of
p at h o g e n 's
at t a c h m e n t t o, o r
r e c o g n i t i o n o f, h o s t
Arildone
Pleconaril
Human
cell
membrane
Inhibit ion of
DNA o r RNA
s yn t h e s i s
Actinomycin
Nucleotide analogs
Quinolones
Rifampin

Figure 10.2
Microbiology with diseases by
Taxonomy

Inhibition of cell wall


synthesis; Penicillins
Cephalosporins
Vancomycin
Bacitracin
Isoniazid
Ethambutol
Echinocandins
(antifungal)

Inhibit ion of
prot ein
syn t h e s i s
Aminoglycosides
Tetracyclines
Chloramphenicol
Macrolides
Di s r u p t i o n o f
c yt o p l a s m i c
m em brane
Polymyxins
Polyenes
(antifungal)
Inhibit ion of general
m e t a b o l i c p at h w a ys
Sulfonamides
Trimethoprim
Dapsone

Mechanisms of Antimicrobial
Drugs

Inhibition of cell wall synthesis


(Peptidoglycan synthesis).

Injure plasma membrane integrity.

Interfere with Nucleic acid and Protein


synthesis.
Interfere with general metabolite synthesis (eg;
Folic acid).

Inhibition of pathogen attachment or recognition


sites of host.

Inhibition of Bacterial cell wall/


Peptidoglycan synthesis.
Peptidoglycan; major structural component of
the bacterial cell wall.
Macromolecule composed of alternating chains
of N- acetylglucosamine (NAG) and Nacetylmuramic acid (NAM), cross-linked.
NAG
NA
M
NAG-NAM
chain

Crossbridge
between
NAM
and NAM

New NAG and NAM


subunits

Growth

A bacterial cell wall is made of peptidoglycan,


which is made of NAG-NAM chains that are
cross-linked by peptide bridges between the
NAM subunits.

New NAG and NAM subunits are inserted into the wall by
enzymes, allowing the cell to grow. Other enzymes link new
NAM subunits to old NAM subunits with peptide cross-links.

Figure 10.3a-b Bacterial cell wall synthesis; Microbiology diseases by Taxonomy

Inhibition of peptidoglycan (PTG) synthesis

Most common antimicrobials prevent cross-linkage of NAM


subunits.
Beta-lactams are most prominent in this group.
Functional groups are beta-lactam rings.
Beta-lactams bind to enzymes that cross-link NAM subunits.
Bacteria have weakened cell walls and eventually lyse.

Figure 10.3a-b Bacterial cell wall synthesis; Microbiology diseases by Taxonomy

Penicillin G
(natural)

New crosslinks inhibited


betaby
lactam

Methicillin
(semisynthetic)

Penic illi ns

Cephalothin
(natural)
Cephalos por ins

Previousl
y formed
cross-link

Growt
h
Beta-lactam interferes with the linking enzymes, and NAM
subunits remain unattached to their neighbors. However,
the cell continues to grow as it adds more NAG and NAM
subunits.

The cell bursts from osmotic pressure


because the integrity of peptidoglycan is not
maintained.

Inhibitors of nucleic acid synthesis

Several drugs/antimicrobial nucleoside analogs (ANAs), block


DNA replication or RNA transcription of pathogen.

ANA Interfere with function of nucleic acids.


ANAs have ddistort shapes of nucleic acid molecules,
therefore they prevent replication, transcription, or
translation.

Most often used against viruses; Viral DNA polymerases


more likely to incorporate these analogs, as they have rapid
DNA synthesis compared to human.

Nucleosides and some of their antimicrobial analogs


AZT: Antiviral drug;
Anti AIDS drug
Viral DNA
polymerase is
more likely to
Include ANAs to its
DNA or RNA.
This distort viral
nucleic acids and
prevents further
cellular
Functions.

Inhibitors of bacterial nucleic acid


synthesis; target enzymes
Quinolones and fluoroquinolones (synthetic
drugs/antibiotics)

Act against prokaryotic DNA specifically


Inhibit DNAgyrase, enzyme involve in
bacterial replication

Antifungal drugs
Much more problematic (eukaryotes!)
Very few available drugs , and the few must focus on
Disruption of cell ergosterol (instead of cholesterol in human
cell membranes).
Inhibition of chitin cell wall structures.
Selective inhibition of fungal mitosis difficult!).

2013 John Wiley & Sons, Inc.


All rights reserved.

Antiviral drugs
Tricky because viruses often use host cell
processes; If you inhibit a host cell process,
toxicity will be HIGH.
Common mechanisms involves Inhibition of
nucleic acid synthesis
Often through nucleoside/nucleotide
analogues (AZT, acyclovir).
Inhibition of virus life cycle steps .

2013 John Wiley & Sons, Inc.


All rights reserved.

Antimicrobial
drug
resistance
time line:

2013 John Wiley & Sons, Inc.


All rights reserved.

Resistance to Antimicrobial Drugs


The Development of Resistance in
Populations
Some pathogens are naturally
resistant
Resistance by bacteria acquired in
two ways
New mutations of chromosomal genes.
Acquisition of resistance genes; R plasmids
via transformation, transduction, and
conjugation (horizontal gene transfer).

The development of a resistant


strain of bacteria.

Drug-sensitive cells

Drug-resistant
mutant
Remainin
g
Populatio
n grows
over time

Exposur
e to
drug

Populat ion of m i c r obial c e lls

Sens it i ve c ells inhibit ed b y ex pos ur e t o dr ug

Figure 10.15 Microbiology with Diseases by Taxonomy .

Mo s t c e lls now r es is t a nt

Mechanisms of Resistance
At least seven mechanisms of microbial resistance
Production of enzyme that destroys or
deactivates drug
Slow or prevent entry of drug into the cell
Alter target of drug so it binds less effectively
Alter their own metabolic chemistry
Pump antimicrobial drug out of the cell before it can
act
Bacteria in biofilms can resist antimicrobials
Mycobacterium tuberculosis produces MfpA protein

Molecular mechanisms of resistance

Production of enzymes that


destroys/deactivates drugs
Certain bacteria produce enzymes; eg;
-lactamases (penicillinase) and inactivate
-lactam antibiotics; penicillin.
Lactam ring

Penicilli
n

-lactamase
(penicillinase) breaks
this bond
Figure 10.16 Microbiology with Diseases by
Taxonomy

Inactive
penicillin

You learned about/


Summary:
Diversity of antimicrobial and antibiotics.
Mechanisms of action of antimicrobials.
Some examples of action of antibiotics.
Antimicrobial Drug Resistance. Different
mechanisms of resistance.

Preparing for the final Exam Essay


Question
a) What are antimicrobials? Briefly discuss
their origin and what you understand by
the term selective toxicity?
b) Describe two mechanisms of action of
antimicrobials, include an example of
antimicrobial/antibiotic in each
mechanism.
(100 marks)

Useful reading;
Brock Biology of Microorganisms,
Microbiology with Diseases by
Taxonomy on Antibiotics and
antibiotic drug resistance.
Other mechanisms of action of
Antimicrobials;

Inhibition of Protein Synthesis.


Bacterial ribosomes are
an excellent target for ST.

Different in structure from


eukaryotic ribosomes.
Prokaryotic ribosomes
are 70S (30S and
50S)
Eukaryotic ribosomes
are 80S (40S and
60S)
Drugs selectively target
steps in
bacterial
translation.
Eg. Macrolides bind near

Steps in Translation/Protein
Synthesis

1
4

Inhibition of Metabolic Pathways


Sulfonamides; Antimetabolic drugs, inhibits the
bacterial nucleic acid synthesis via inhibiting the Folic
Acid (essential bacterial metabolite) synthesis.
Sulfonamides are a structural analog (and
competitive inhibitor) for PABA, a necessary
precursor for synthesis of nitrogenous bases.

2013 John Wiley & Sons, Inc.

The antimetabolic action of sulfonamides in


inhibiting nucleic acid synthesis.

PABA
Sulfamethoxazole

Sulfisoxazole

Sulfanilamide

Par a-a m i nobenzoic ac id (PA B A ) and it s s t r u c t ur a l analogs , t he s ulf ona m i d es


PABA

Enzyme

Dihydrofolic
acid

Enzyme
acid (THF)

PABA
Other
substrates

Purine and
pyrimidine
nucleotides

Tetrahydrofolic Enzymes

Enzymes

DNA and RNA

PABA
Dihydrofolic
acid

Other
substrates

Dihydrofolic acid
not produced

Active site
Enzyme
Role of PA B A in f olic ac id s yn t hes is in b ac t er ia
and pr ot ozoa

Figure 10.6 Microbiology Diseases by Taxonomy

Enzyme
Inh ibit ion of f olic ac id s ynt hes is by s ulf ona m i de