Anda di halaman 1dari 32

Mechanisms of Molecular

Antibiotic Resistance

Objectives
History of antibiotics
Definition of antibiotic resistance
Why antibiotic resistance is a concern
?
Why is it important?
How antibiotics work ?
Mechanisms of resistance to
antibiotics ?
Control

Introduction
Throughout history there has been a
continual battle between human
beings and multitude of microorganisms that cause infection and
disease

History

Nobel Lecture, December 11, 1945

Sir Alexander Fleming


The Nobel Prize in Physiology or
Medicine 1945

-1928: Penicillin first discovered by Alexander

Fleming

-Chain and Florey, helped develop penicillin into


a widely available medical product

History

Nobel Lecture, December 11, 1945

Sir Alexander Fleming


The Nobel Prize in Physiology or
Medicine 1945

Fleming himself warned of the danger of


resistance

It is not difficult to make microbes


resistant to penicillin in the laboratory by
exposing them to concentrations not
sufficient to kill them, and the same thing
has occasionally happened in the body
and by exposing his microbes to nonlethal quantities of the drug make them
resistant.

Antibiotic Resistance
Defined as micro-organisms that are
not inhibited by usually achievable
systemic concentration of an
antimicrobial agent with normal
dosage schedule and / or fall in the
minimum inhibitory concentration
(MIC) range.

Mechanisms of action of antibiotics

Drug Resistance
Drug resistance occurs in :
BACTERIAANTIBIOTIC
RESISTANCE
Endoparasites
VirusesResistance to
antiviral drugs
Fungi
Cancer cells

Why resistance is a
concern ?
Resistant organisms lead to
treatment failure .
Increased mortality .
Resistant bacteria may spread in
Community.
Low level resistance can go
undetected.
Added burden on healthcare costs .
Threatens to return to pre-antibiotic
era .

Antibiotic Resistance
Some microorganisms may born resistant, some achieve
resistance by mutation or some have resistance thrust upon
them by plasmids

Intrinsic Resistance

It occurs naturally.
1. Lack target :
No cell wall; innately resistant to
penicillin
2. Innate efflux pumps:
Drug blocked from entering cell or
export of drug (does not achieve
adequate internal concentration).
Eg. E. coli, P. aeruginosa
3. Drug inactivation:
Cephalosporinase in Klebsiella

Acquired resistance
Mutations
It refers to the change in DNA structure
of the gene.
Occurs at a frequency of one per ten
million cells.
Eg.Mycobacterium.tuberculosis,Mycoba
cterium lepra , MRSA.
Often mutants have reduced
susceptibility

Plasmids
Extra chromosomal genetic elements can replicate
independently and freely in cytoplasm.
Plasmids which carry genes resistant ( r-genes)
are called R-plasmids.
These r-genes can be readily transferred from one
R-plasmid to another plasmid or to chromosome.
Much of the drug resistance encountered in clinical
practice is plasmid mediated

Mechanisms of Resistance Gene Transfer

Transfer of r-genes from one


bacterium to another
Conjugation
Transduction
Transformation
Transfer of r-genes between
plasmids within the bacterium
By transposons
By Integrons

Transfer of r-genes from one bacterium to


another
Conjugation : Main mechanism for spread
of resistance
The conjugative plasmids make a
connecting tube between the 2 bacteria
through which plasmid itself can pass.
Transduction : Less common method
The plasmid DNA enclosed in a
bacteriophage is transferred to another
bacterium of same species. Seen in
Staphylococci , Streptococci
Transformation : least clinical problem.
Free DNA is picked up from the

Mechanisms of Resistance Gene


Transfer
Transposons

Transposons are sequences of


DNA that can move around
different positions within the
genome of single cell.

The donor plasmid containing


the Transposons, co-integrate
with acceptor plasmid. They
can
replicate
during
cointegration

Both plasmids then separate


and each contains the r-gene
Eg ; Staphylococci,Enterococ
carrying the transposon.

Mechanisms of Resistance Gene Transfer


Integrons
Integron is a large mobile
DNA
that
can
spread
Multidrug resistance
Each Integron is packed
with multiple gene casettes,
each
consisting
of
a
resistance gene attached to
a small recognition site.
These
genes
encode
several bacterial functions
including
resistance
and
virulence.

Biochemical mechanisms of
antibiotic resistance
Prevention of drug accumulation in the
bacterium
Modification/protection of the target site
Use of alternative pathways for metabolic
/ growth requirements
By producing an enzyme that inactivates
the antibiotic

Decreased permeability: Porin Loss


Antibiotics normally enter bacterial cells via porin channels
in the cell wall

Antibiotic
Porin channel
into organism

Cell wall

Interior of organism

Decreased permeability: Porin Loss


New porin channels in the bacterial cell wall do not allow
antibiotics to enter the cells

Antibiotic

New porin channel


into organism

Cell wall

Interior of organism

Structurally modified antibiotic


target site
Antibiotics normally bind to specific binding proteins on the
bacterial cell surface

Antibiotic

Binding

Target site

Cell wall

Interior of organism

Structurally modified antibiotic target site


Antibiotics are no longer able to bind to modified binding proteins
on the bacterial cell surface

Antibiotic
Modified target site

Cell wall

Changed site: blocked binding

Interior of organism

Antibiotic inactivation

Inactivating enzymes target antibiotics

Antibiotic
Enzyme

Binding

Target site

Cell wall

Interior of organism

Antibiotic inactivation
Enzymes bind to antibiotic molecules

Enzyme
binding

Antibiotic

Enzyme

Binding

Target site

Cell wall

Interior of organism

Antibiotic inactivation

Enzymes destroy antibiotics or prevent binding to target sites


Antibiotic
destroyed

Antibiotic altered,
binding prevented

Antibiotic

Enzyme

Target site

Cell wall

Interior of organism

Timeline of Antibiotic Resistance

Strategy to Prevent antibiotic


Resistance
Develop new antibiotics.
Appropriate use of the existing
antibiotics
Phage therapy.
Use of the lytic enzymes found in
mucus and saliva.

References
-Medicinska Mikrobiologija Sa Imunologijom i
Parazitologijom-Mirsada Hukic
-http://en.wikipedia.org/wiki/Scientific_method
-http://www.slideshare.net/nasertadvi/antibioticresistance-14709382?related=2
-http://www.who.int/drugresistance/amr_q&a.pdf
-http://www.powershow.com/view4/53f288NDBiN/ANTIMICROBIAL_RESISTANCE_powerpoint_ppt
_presentation

Worked by :

Adnan Fojnica