Mechanisms of bacterial

resistance
Dr. Hawa
DC 500
For DDS 2017/2018
• Microorganisms have existed on the earth for
more than 3.8 billion years
• They exhibit the greatest genetic and
metabolic diversity.
• They are an essential component of the
biosphere
• Serve an important role in the maintenance
and sustainability of ecosystems.
• In order to survive, bacteria have evolved
mechanisms that
• enable them to respond to selective
pressure exerted in
– various environments
– competitive challenges
• The disease-causing microorganisms:
–particularly have been vulnerable
to man’s selfishness for survival
–who has sought to deprive them of
their habitat using antimicrobial
agents.
• These microorganisms have
responded by
–developing resistance
mechanisms to fight off this
offensive action.
• Currently, antimicrobial resistance
among bacteria, viruses, parasites,
and other disease-causing
organisms is
a serious threat to infectious
disease management globally
 History of resistance
• After the discovery of penicillin in 1940,
– number of treatment failures and
–occurrence of some bacteria
(staphylococci) which were no longer
sensitive to penicillin were noticed.
• This marked the beginning of the
error of antimicrobial resistance.
 History of resistance
• Increasing prevalence of resistance has been
reported in world wide
• This has been attributed to
– changing microbial characteristics,
– selective pressures of antimicrobial use, and
– societal and technological changes
• that enhance the development and transmission of
drug-resistant organisms.
 History of resistance
• Although antimicrobial resistance is a
natural biological phenomenon
–often enhanced infectious agents’
adaptation to exposure to
antimicrobials used in humans or
agriculture and
–widespread use of disinfectants at the
farm and the household levels
• Therefore it is accepted that:
–antimicrobial use is the single
most important factor
responsible for increased
antimicrobial resistance
 Reasons for increasing resistance
levels
1. suboptimal use of antimicrobials for
prophylaxis and treatment of
infection,
2. Non-compliance with infection-
control practices,
3. Prolonged hospitalization due to
terminal care conditions
 Reasons for increasing resistance
levels
4. Increased number and duration of
intensive care-unit stays as a result of
advances in medical technologies in mng.
and dx,
5. Multiple co-morbidities in case of
hospitalized patients and Immuno-
comprimized patients,
6. Increased use of invasive devices and
catheters in patients
 Reasons for increasing resistance
levels
7. Transfer of colonized patients from hospital
to hospital,
8. Grouping of colonized patients in long-term-
care facilities,
9. Rise in antibiotic (antiseptics Dettol) use in
agriculture and household chores, and
10.Increasing national and international travel.
Mechanisms of Action of Antimicrobial
Agents
• In order to appreciate the mechanisms of
resistance,
• it is important to understand how
antimicrobial agents act
1. Inhibition of the cell wall synthesis
2. Inhibition of ribosome function
3. Inhibition of nucleic acid synthesis
4. Inhibition of folate metabolism
5. Inhibition of cell membrane function
 Mechanisms of Antimicrobial
Resistance
Resistance can be described in two
ways:
a) intrinsic or natural
b) acquired resistance
 Intrinsic or natural
• microorganisms naturally do not posses
target sites for the drugs and therefore the
drug does not affect them or
• they naturally have low permeability to those
agents because of the differences in the
chemical nature of the drug and
• the microbial membrane structures
especially for those that require entry into
the microbial cell in order to effect their
action
 Acquired resistance
Mechanisms for acquired resistance
– the presence of an enzyme that inactivates the
antimicrobial agent
– the presence of an alternative enzyme for the
enzyme that is inhibited by the antimicrobial
agent
– a mutation in the antimicrobial agent’s target,
which reduces the binding of the antimicrobial
agent
 acquired resistance
Mechanisms for acquired resistance
• post-transcriptional or post-translational
modification of the antimicrobial agent’s
target, which
• reduces binding of the antimicrobial agent
reduced uptake of the antimicrobial agent
• active efflux of the antimicrobial agent
 acquired resistance
Mechanisms for acquired resistance
• overproduction of the target of the
antimicrobial agent
• expression or suppression of a gene in vivo in
contrast to the situation in vitro
• previously unrecognized mechanisms
Resistance to b-Lactam Antibiotics
• b-Lactam antibiotics are a group of antibiotics
characterized by
– possession of a b-lactam ring
– include penicillins, cephalosporins, carbapenems,
oxapenams, and cephamycins.
• The penicillins are one of the most commonly
used antibiotics in developing countries because
of their
– ready availability and
– relatively low cost.
• Resistance to b-lactams in many bacteria
is usually due to
–the hydrolysis of the antibiotic by a b-
lactamase or
–the modification of PBPs or cellular
permeability
 Tetracycline Resistance
• Tetracyclines are another of
– the very commonly used antimicrobial agents in
both human and veterinary medicine in
developing countries
• because of their
– availability and
– low cost as well as
– low toxicity and
– broad spectrum of activity
• Resistance to these agents occurs mainly
through three mechanisms (Roberts, 1996)
– Efflux of the antibiotics,
– Ribosome protection, and
– Modification of the antibiotic.
• These tetracycline resistance determinants are
widespread in different microorganisms
 Chloramphenicol Resistance
• Chloramphenicol
– binds to the 50S ribosomal subunit and
– inhibits the peptidyl transferase step in protein
synthesis.
• Resistance to chloramphenicol is generally due
– to inactivation of the antibiotic by a
chloramphenicol acetyltransferase
 Multidrug Resistance
• Multidrug resistance among many organisms
has become a big challenge to infectious
disease management.
• It is increasingly being reported in bacteria
• often mediated by genetic mobile elements
such as plasmids, transposons, and integron