ENUGU STATE UNIVERSITY OF SCIENCE AND
TECHNOLOGY
FACULTY OF BASIC MEDICAL SCIENCES
DEPARTMENT OF MEDICAL BIOCHEMISTRY
MCBH 323
DRUG RESISTANCE
BY
MARTINS OBINNA OGUGOFOR
INTRODUCTION
Drug resistance could be seen as the ability of a
disease-causing organism such as bacteria,
protozoa, fungi and viruses to continue
multiplying despite the presence of drugs that
usually kill them.
It could also be seen as the cell tolerance to one
or multiple drugs ultimately leading to treatment
failure.
Drug resistance could also occur during caner
treatment where cancer cells develop resistance
to structurally and functionally unrelated
compounds.
TYPES OF DRUG RESISTANCE
Intrinsic drug resistance
Extrinsic drug resistance
INTRINSIC DRUG RESISTANCE
o Intrinsic resistance is resistance that is naturally present in the
microorganism.
o It is a property controlled by chromosomes and is related to the general
physiology of the microorganism.
o The differences in resistance to antimicrobials occurring among different
types, genera, species, and strains of microorganisms under identical
environmental conditions and antimicrobial concentrations are most likely
controlled innately.
EXTRINSIC DRUG RESISTANCE
Acquired/extrinsic resistance results when a microorganism
acquires the ability to resist the activity of a particular
antimicrobial agent to which it was previously susceptible.
This could be due to the mutation of genes involved in normal
physiological processes and cellular structures, from the
acquisition of foreign resistance genes, or from a combination of
these two mechanisms.
Successful gene change and/or exchange may involve mutation
or horizontal gene transfer by transformation, transduction, or
conjugation.
ANTIBIOTIC RESISTANCE
TYPES OF ANTIBIOTIC RESISTANCE
o Natural (IntrInsic, Structural) resistance: This kind of resistance is
caused by the structural characteristics of bacteria and it is not
associated with the use of antibiotics.
o It develops as a result of the natural resistance, or the microorganisms
not having the structure of the target antibiotic, or antibiotics not
reaching to its target due to its characteristics.
o For example, Gram negative bacteria vancomycin does not pass through
the outer membrane of Gram-negative bacteria, and thus making the
organism resistant to vancomycin.
o Cell wall-less cell Mycoplasma and Ureaplasma are naturally resistant to
beta-lactam antibiotics that inhibit the cell wall synthesis
Acquired resistance: This kind of resistance occurs due to
mainly structures of chromosome or extrachromosomal
(plasmid, transposon, etc.).
Such mutations may occur according to some physical
(ultraviolet, etc.) and chemical factors. This can be a result of
structural changes in bacterial cells.
The result may be reduced permeability of bacterial drug or
changes of the target of the drug may be in the cell.
Streptomycin, aminoglycosides, erythromycin, lincomycin can
develop resistance against these types.
Extrachromosomal resistance: This depends on extrachromosomal
genetic elements that can be transferred in various ways like
plasmids, transposons and integrons.
Plasmids are extrachromosomal DNA fragments that can replicate
independently from chromosome. Plasmid genes are usually
responsible for the generation of enzymes which makes antibiotics
inactive.
Resistance genes and plasmids are transmitted to bacterium in
three ways: transduction, transformation, conjugation, and
transposition mechanism.
Transduction can occur via bacteriophage resistance genes;
transformation via DNA binding protein called competence factor;
conjugation via sex pilus between two live bacteria through transfer
of resistance genes.
Antibiotic resistance genes on the chromosome or plasmid is
interconnected with each other and located near the start of specific
units of integration is called integrons.
Cross Resistance: Cross‐resistance is a resistance to multiple
distinct antimicrobial agents conferred by a single molecular
mechanism.
It occurs when antimicrobials share a route of access to the
cytoplasm, bind the same target or are involved in the same
pathway leading to the inhibition of growth or cell death
Co-resistance between erythromycin, neomycin-kanamycin is
normally observed in antibiotics whose structures are similar.
Sometimes it can also be seen in a completely unrelated drug
groups. There is an example of cross-resistance between
erythromycin-lincomycin. This could result from chromosomal
or extrachromosomal transfer.
cross-resistance in cancer treatment is a type of acquired
resistance, that is developed as a reaction to a drug and
results in resistance to other drugs
Multi-drug resistance: Multidrug-resistant organisms are usually bacteria that
have become resistant to the antibiotics used to treat them.
This means that a particular drug is no longer able to kill or control the bacteria.
Inappropriate use of antibiotics for therapy resulted in the selection of pathogenic
bacteria resistant to multiple drugs.
Multidrug resistance in bacteria involves two mechanisms. Bacteria may
accumulate multiple genes, each coding for resistance to a single drug.
This type of resistance occurs typically on resistance (R) plasmids. This could also
result from the increased expression of genes that code for multidrug efflux
pumps, enzymatic inactivation, changes.
If a bacterial strain is resistant to three or more classes of antimicrobials, it is
considered as multi-drug resistant.
If the strain is resistant to all but one or two antibiotic groups, they are considered
as extensively-drug-resistant
if the strain is resistant to all available antibiotic, they are classified as pan-drug-
resistant.
For instance, multidrug resistance (MDR) Acinetobacter
species (spp.) are resistant to antimicrobial agents such as
all penicillins and cephalosporins (including inhibitor
combinations), fluroquinolones, and aminoglycosides).
Extensive drug resistant (XDR) Acinetobacter spp.’ are
resistant to carbapenems.
Pandrug resistant or pan-resistant (PDR) Acinetobacter
spp. Ae resistant to polymyxins (colistin) and tigecycline
o Some examples of strategies adopted in intrinsic drug resistance by
some microorganisms include the following:
o Cellular barriers, which prevent entry or uptake of disinfectants
(e.g., spore coat and cortex in sporogenous bacteria, waxy cell wall
in mycobacteria, outer membrane of Gram-negative bacteria, and
teichoic acids in Gram-positive bacteria).
o Cellular efflux which pumps compounds out of the cell, and thus
reduces the efficacy of a number of microbicides, including
benzalkonium chloride and related compounds, phenolics parabens,
and intercalating agents.
o Lack of a biochemical target for antimicrobial attachment or
microbial inactivation, and some microbes have enzymes which
inactivate microbicide.
CLASSIFICATION OF FAMILIES OF EFFLUX PUMPS IN BACTERIA
BASED ON STRUCTURE AND ENERGY SOURCE
ATP-binding cassette (ABC)family
Multidrug and toxic compound extrusion (MATE) family
Small multidrug resistance (SMR) family
Major facilitator superfamily (MFS)
Resistance-nodulation-cell division (RND)
THE ABC EFFLUX FAMILY
It contains both uptake and efflux transport systems. The members of this
family are unique in that they use energy derived from ATP hydrolysis.
These pumps transport amino acids, drugs, ions, polysaccharides, proteins,
and sugars.
Bacterial ABC transporters usually are made up of six transmembrane
segments (TMS) consisting of α-helices, function in the membrane in pairs,
either as homodimers or heterodimers, and work in conjunction with
cytoplasmic ATPases.
These pumps have fairly specific substrates, and there are very few found in
clinically significant bacteria.
An example of ABC pump is found in Vibrio cholerae (VcaM), and is capable of
transporting fluoroquinolones and tetracycline.
THE MATE EFFLUX FAMILY
This uses a Na+ gradient as the energy source, and efflux cationic dyes,
and most efflux fluoroquinolone drugs.
Some MATE pumps have also been shown to efflux some aminoglycosides.
Other substrates for these pumps may have unrelated chemical structures.
These pumps are made up of twelve transmembrane segment. Very few of
these have been characterized in bacteria, and most are found in gram
negative organisms.
The first to be characterized was the NorM pump from chromosomal DNA
in Vibrio parahaemolyticus.
Other clinically significant bacteria that have NorM pumps
include Neisseria gonorrhoeae and Neisseria meningitidis
THE SMR EFFLUX FAMILY
This family of pumps are energized by the proton-motive force (H +). They are
hydrophobic, and efflux mainly lipophilic cations. They have a very narrow
substrate range.
The genes for these pumps have been found in chromosomal DNA and on
plasmids and transposable elements.
These pumps are made up of four transmembrane segment and function as
asymmetrical homotetramers.
Drug efflux has only been seen in a few of these pumps, and these most
commonly confer resistance to β-lactams and some aminoglycosides.
Examples of SMR pumps are seen in Staphylococcus epidermidis (the SMR
pump which transports ampicillin, erythromycin and tetracycline)
and Escherichia coli (the EmeR pump which transports vancomycin,
erythromycin, and tetracycline
THE MFS EFFLUX FAMILY
This family catalyze transport via solute/cation (H+ or Na+) symport or
solute/H+ antiport.
They are involved in the transport of anions, drugs (e.g. macrolides and
tetracycline), metabolites (e.g. bile salts), and sugars.
The MFS pumps have the greatest substrate diversity as a group, yet
individually tend to be substrate specific. Examples of this substrate specificity
include Acinetobacter baumannii having separate MFS pumps for erythromycin
(SmvA) and chloramphenicol (CraA and CmlA), and Escherichia coli having
separate MFS pumps for macrolides (MefB), fluoroquinolones (QepA), and
trimethoprim (Fsr).
There are few examples of MFS pumps with a slightly broader substrate
specificity, such as in the NorA pump in Staphylococcus aureus which
transports fluoroquinolones and chloramphenicol (these antimicrobials are
mostly transported by MFS pumps), or the S. aureus LmrS pump which
transports linezolid, erythromycin, chloramphenicol, and trimethoprim.
THE RND EFFLUX FAMILY
They catalyze substrate efflux via a substrate/H+ antiport mechanism, and are
found in numerous gram negative bacteria.
They are involved in the efflux of antibiotics (all are multi-drug transporters),
detergents, dyes, heavy metals, solvents, and many other substrates.
Some of these pumps may be drug or drug class specific (Tet pump—tetracycline;
Mef pump—macrolides).
Other RND pumps transport various drugs, such as the MexAB-OprM pump
in Pseudomonas aeruginosa that confers intrinsic resistance to β-lactams,
chloramphenicol, tetracycline, trimethoprim, sulfamethoxazole, and some
fluoroquinolones.
The most widely studied RND pump is the AcrAB-TolC pump in Escherichia coli,
that confers resistance to penicillins, chloramphenicol, macrolides,
fluoroquinolones, and tetracycline.
DRUG RESISTANCE IN CANCER CELLS
INTRINSIC AND EXTRINSIC FACTORS IN CANCER DRUG
RESISTANCE
Inactivation of anticancer agents
Increased release of the drugs out of the cell
Reduced absorption of drugs
Inhibition of apoptosis
Change in drug metabolism
Change in drug target
DNA repair mechanisms
Gene amplification – eg. Methotrexate resistance
Epigenetic alterations- DNA methylation and histone
alterations
