Antimicrobial Resistance

Lecture No (9)
By
Dr. Ahmed El-Baz
Antimicrobial resistance

is the ability of microorganism to survive

and reproduce in the presence of
antimicrobial does that were previously
thought effective against them
 Cross Resistance:

Cross resistance
single mechanism confers
resistance to multiple
antimicrobial agents, is
commonly seen with closely
related antimicrobial agents
e.g. Beta lactamase enzymes for
B-lactams.
 Multiple resistance

multiple resistance
that multiple mechanisms are involved
to multiple antimicrobial agents is seen
with unrelated antimicrobial agents.
Lead to MDR= Multiple drug resistance
 Multiple-drug resistance (MDR):
Non‐susceptibility to at least one agent in three or more
antimicrobial categories.

Extended-drug resistance (EDR):

Non‐susceptibility to at least one agent in all but two or fewer
antimicrobial categories still effective (i.e. bacterial isolates remain
susceptible to only one or two categories).

Pan-drug resistance (PDR):

Non‐susceptibility to all agents in all antimicrobial categories that
used in empirical therapy (can be susceptible to one or two
antimicrobial agents only).
• 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 R-plasmids via transformation, transduction,
and conjugation.
• Mechanisms of Resistance
– At least five mechanisms of microbial resistance
1. Production of enzyme that destroys or deactivates drug
2. Slow or prevent entry of drug into the cell
3. Alter target of drug so it binds less effectively
4. Alter their metabolic chemistry
5. Pump antimicrobial drug out of the cell before it can act
(Efflux pump).
1- Production of enzyme that destroys or deactivates drug

2- Slow or prevent entry of drug into the cell

Decreased uptake of the drug
Alterations in porin proteins decrease permeability of
cells Prevents certain drugs from entering
3- Alter target of drug so it binds less effectively

Minor structural changes in antibiotic target can

prevent binding
Ex: Changes in ribosomal RNA prevent
aminoglycosides from binding to ribosomal
subunits

4- Alter their metabolic chemistry

Taking alternative pathway other than the primary metabolic way
5- Pump antimicrobial drug out of the cell before it can act
Some organisms produce efflux pumps so increases
overall capacity of organism to eliminate drug
Enables organism to resist higher
concentrations of drug
 Mechanism of resistance to common antimicrobial
agents
1- Betalactam
• Modification of target sites (Penicillin binding
proteins(Transpeptidase)
• Decreased accumulation (Efflux pump)
• Enzymatic inactivation (Beta-lactamase )
 2- Non Betalactam antibiotics

A- Vancomycin
Alter target of drug so it can not bind to the new target
• D-alanyl-D-alanine residue
↓
D-alanyl-D-lactate moiety

• vancomycin cannot bind to this peptide

B- Bacitracin
Mechanism of action: Inhibits dephosphorylation in
cycling of bactoprenol that transfers peptidoglycan
subunits to the growing cell wall
Mechanism of Resistance: Increase synthesis of the
bactoprenol molecule
 3- Polymyxins
• The loss of outer membrane porin proteins, which
involved in the penetration of polymyxin B.
• A reduction in binding of polymyxin to the cell envelope
as a result of changes in lipid and LPS composition.
4- Aminoglycosides
• Productionof aminoglycoside inactivating enzyme that
chemically modifies drug (the most common mechanism)
• Reduced uptake or decreased cell permeability:

• Altered ribosome binding Sites by mutations binding. This

mechanism is very common for streptomycin√√
 5- Tetracyclines

Cells become resistant to tetracycline by at least three

mechanisms:
1. Enzymatic Inactivation is the rarest type of resistance,
2. Efflux: Resistance due to decreased accumulation by
bacterial cells.
3. Ribosomal protection: through certain reactive protein
include:
- blocking tetracyclines from binding to the ribosome.
- binding to the ribosome and distorting the structure
to still allow t-RNA binding while tetracycline is bound
 6- Chloramphenicol
There are three mechanisms of resistance to
chloramphenicol:
• Reduced membrane permeability.
• Mutation of the 50S ribosomal subunit which lead to
structural changes in antibiotic target therefore prevent
binding.
• Production of chloramphenicol acetyltransferase which
deactivate the drug.
7- Macrolides
• Structural changes in the target ribosomal RNA.
• Production of drug-inactivating enzymes (esterases or
kinases).
• Production of active ATP-dependent efflux proteins that
transport the drug outside of the cell.
 8- Quinolone
Resistance due to alteration of DNA gyrase.
9- Rifampcins
Resistance due to mutation coding RNA polymerase
10- Sulfonamides and trimethoprim
Resistance due to plasmid codes for enzyme that has
lower affinity to drug
• Retarding Resistance
- Maintain high concentration of drug in patient for
sufficient time
• Kills all sensitive cells and inhibits others so immune
system can destroy
- Use antimicrobial agents in combination
• Synergism vs. antagonism

- Use antimicrobials only when necessary

- Develop new variations of existing drugs

Fourth generation drugs

- Search for new antibiotics, semi-synthetics, and

synthetics
Design drugs complementary to the shape of microbial
proteins to inhibit them
Mechanisms drug resistance

17
 Bacterial culture sensitivity

1. Write your comment about the most preferable antimicrobial for this case?
2. Write the type of resistance in this microorganism?
3. Expect the type of infection (organ that affected in the body)?
 Primary Bacterial culture

1. Determine the type of microorganism that detected in culture?

2. Expect the suitable antimicrobial agent that may be effective?
 Case report

An 86-year-old male presented to the emergency department with a chief

complaint of an ankle injury and a foot non-healing ulcer sustained from
a drill accident 2 months prior to his visit in our hospital. The patient
also related that he had diabetes for approximately 13 years without any
treatment to control the disease. During the initial consultation, the
patient related no use of any antibiotic therapy for his non-healing
wound to the right foot. The patient was admitted to the hospital for
further investigations.

1. Discuss the required medical action from microbiological view?

2. Expect the required drugs for this case?