Bac 6

Mechanisms of Antibacterial Resistance
(Part I)
Dr. Charitha Mendis

Dept. of Medical Laboratory Science,
Faculty of Allied Health Sciences,
University of Peradeniya
Objectives
• At the end of this lecture students should be

able to
– explain the concept of drug resistance
– describe how microorganisms develop or acquire
drug resistance
– describe the different mechanisms of
antimicrobial drug resistance
Introduction
• Antimicrobial resistance is not a new phenomenon.
• In nature, microbes are constantly evolving in order to
overcome the antimicrobial compounds produced by
other microorganisms.
• Human development of antimicrobial drugs and their
widespread clinical use has simply provided another
selective pressure that promotes further evolution.
• There are several important factors that can accelerate
the evolution of drug resistance.
• These include the overuse and misuse of antimicrobials,
inappropriate use of antimicrobials, sub therapeutic
dosing, and patient noncompliance with the
recommended course of treatment.
Introduction
What is selective pressure?
• The influence exerted by some factor (such as an antibiotic)
on natural selection to promote one group of organisms
over another.
• In the case of antibiotic resistance, antibiotics cause a
selective pressure by killing susceptible bacteria, allowing
antibiotic-resistant bacteria to survive and multiply.
• Selection pressure can be regarded as a force that causes a
particular organism to evolve in a certain direction.
• Organisms have many different phenotypes, or observable
characteristics, many are neutral.
• A selective pressure is any reason for organisms with certain
phenotypes to have either a survival benefit or
disadvantage.
• Selective pressures leads natural selection.
Introduction
(https://www.reactgroup.org/toolbox/understand/antibiotic-resistance/mutation-and-selection/)
Introduction
• Exposure of a pathogen to an antimicrobial compound
can select for chromosomal mutations conferring
resistance, which can be transferred vertically to
subsequent microbial generations and eventually
become predominant in a microbial population that is
repeatedly exposed to the antimicrobial.
• Alternatively, many genes responsible for drug resistance
are found on plasmids or in transposons that can be
transferred easily between microbes through horizontal
gene transfer.
• Transposons also have the ability to move resistance
genes between plasmids and chromosomes to further
promote the spread of resistance.
Mechanisms for Drug Resistance
• There are several common mechanisms for

drug resistance.
• These mechanisms include :
– Drug modification or inactivation
– Prevention of cellular uptake or efflux
– Target modification
– Target overproduction or enzymatic bypass
– Target mimicry
Mechanisms for Drug Resistance
Drug modification or inactivation
• Resistance genes may code for enzymes that
chemically modify an antimicrobial
• As a result of it antimicrobial can be inactivated or
destroyed through hydrolysis.
• Resistance to many types of antimicrobials occurs
through this mechanism.
• For example, aminoglycoside resistance can occur
through enzymatic transfer of chemical groups to the
drug molecule, impairing the binding of the drug to
its bacterial target.
• For β-lactams, bacterial resistance can involve the
enzymatic hydrolysis of the β-lactam bond within the
β-lactam ring of the drug molecule.
Drug modification or inactivation
• Once the β-lactam bond is broken, the drug loses
its antibacterial activity.
• This mechanism of resistance is mediated by β-
lactamases, which are the most common
mechanism of β-lactam resistance.
• Inactivation of rifampin commonly occurs
through glycosylation, phosphorylation, or
adenosine diphosphate (ADP) ribosylation,.
• Resistance to macrolides and lincosamides can
also occur due to enzymatic inactivation of the
drug or modification.
Prevention of Cellular Uptake or Efflux
• Microbes may develop resistance mechanisms that
involve inhibiting the accumulation of an antimicrobial
drug, which then prevents the drug from reaching its
cellular target.
• This strategy is common among gram-negative
pathogens and can involve changes in outer
membrane lipid composition, porin channel selectivity,
and/or porin channel concentrations.
• For example, a common mechanism of carbapenem
resistance among Pseudomonas aeruginosa is to
decrease the amount of its OprD porin, which is the
primary portal of entry for carbapenems through the
outer membrane of this pathogen.
Prevention of Cellular Uptake or Efflux
• Additionally, many gram-positive and gram-negative
pathogenic bacteria produce efflux pumps that
actively transport an antimicrobial drug out of the cell
and prevent the accumulation of drug to a level that
would be antibacterial.
• For example, resistance to β-lactams, tetracyclines,
and fluoroquinolones commonly occurs through
active efflux out of the cell, and it is rather common
for a single efflux pump to have the ability to
translocate multiple types of antimicrobials.
Target Modification
• Because antimicrobial drugs have very specific targets,
structural changes to those targets can prevent drug
binding, rendering the drug ineffective.
• Through spontaneous mutations in the genes
encoding antibacterial drug targets, bacteria have an
evolutionary advantage that allows them to develop
resistance to drugs. This mechanism of resistance
development is quite common.
• Genetic changes impacting the active site of penicillin-
binding proteins (PBPs) can inhibit the binding of β-
lactam drugs and provide resistance to multiple drugs
within this class.
Target Modification
• This mechanism is very common among strains
of Streptococcus pneumoniae, which alter their own
PBPs through genetic mechanisms.
• In contrast, strains of Staphylococcus aureus develop
resistance to methicillin (MRSA) through the
acquisition of a new low-affinity PBP, rather than
structurally alter their existing PBPs.
• Not only does this new low-affinity PBP provide
resistance to methicillin but it provides resistance to
virtually all β-lactam drugs, with the exception of the
newer fifth-generation cephalosporins designed
specifically to kill MRSA.
Target Modification
• Other examples of this resistance strategy include
alterations in
– ribosome subunits, providing resistance to macrolides,
tetracyclines, and aminoglycosides;
– lipopolysaccharide (LPS) structure, providing resistance
to polymyxins;
– RNA polymerase, providing resistance to rifampin;
– DNA gyrase, providing resistance to fluoroquinolones;
– metabolic enzymes, providing resistance to sulfa
drugs, sulfones, and trimethoprim; and
– peptidoglycan subunit peptide chains, providing resistance
to glycopeptides.
Target Overproduction or Enzymatic Bypass
• When an antimicrobial drug functions as an
antimetabolite, targeting a specific enzyme to inhibit
its activity, there are additional ways that microbial
resistance may occur.
• First, the microbe may overproduce the target enzyme
such that there is a sufficient amount of antimicrobial-
free enzyme to carry out the proper enzymatic
reaction.
• Second, the bacterial cell may develop a bypass that
circumvents the need for the functional target
enzyme.
• Both of these strategies have been found as
mechanisms of sulfonamide resistance.
Target Overproduction or Enzymatic Bypass
• Vancomycin resistance among S. aureus has been
shown to involve the decreased cross-linkage of
peptide chains in the bacterial cell wall, which
provides an increase in targets for vancomycin to bind
to in the outer cell wall.
• Increased binding of vancomycin in the outer cell wall
provides a blockage that prevents free drug molecules
from penetrating to where they can block new cell
wall synthesis.
Target Mimicry
• A recently discovered mechanism of resistance called
target mimicry involves the production of proteins
that bind and sequester drugs, preventing the drugs
from binding to their target.
• For example, Mycobacterium tuberculosis produces a
protein with regular pentapeptide repeats that
appears to mimic the structure of DNA.
• This protein binds fluoroquinolones, sequestering
them and keeping them from binding to DNA,
providing M. tuberculosis resistance to
fluoroquinolones.
• Proteins that mimic the A-site of the bacterial
ribosome have been found to contribute to
aminoglycoside resistance as well.
Question 1:
Briefly explain several mechanisms
for drug resistance giving examples.

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Mechanisms of Antibacterial Resistance

Dr. Charitha Mendis

• At the end of this lecture students should be

• There are several common mechanisms for

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