29
tuberculosis and gonorrhea, the fungi that cause yeast infections and the parasites that
cause malaria, are becoming resistant to standard therapies.
The Mechanism of Resistance
Research efforts previously directed toward discovering new antibiotics are now largely
focused on learning the mechanics of bacterial resistance. Bacteria have developed two
types of strategies for circumventing the action of antibiotics: 1) by mutation where
an alteration in a gene produces a change in later generations or 2) by incorporating
exogenous genetic material as described previously in the first reported VRSA case in
Michigan.11 The end result is a decreased or complete lack of susceptibility of the organisms
to antibiotics that were previously effective. While some bacteria have intrinsic resistance
mechanisms that predate the introduction of antibiotics, others have developed resistance
due to many contributing factors, such as overuse, suboptimal dosing, incorrect choice of
antibiotic, incorrect duration of treatment or inappropriate route of administration.
Understanding the mechanisms and effects of mutation can be quite complicated. For
example, fluoroquinolone resistance, in part, “arises from spontaneous mutations in the
genes encoding the enzyme subunits. With GyrA and ParC units of the resistant bacteria,
amino acid changes are generally localized to a region of the enzyme in the amino termi-
nus that contains the active site, a tyrosine that is covalently linked to the broken DNA
strand during enzyme action. For the GyrB and ParE subunits of resistant bacteria, amino
acid changes, when present, are usually localized to the midportion of the subunit in a
domain involved in interactions with their complementary subunits.”12 In simpler terms,
bacteria can become resistant to fluoroquinolones by making one or a few mutations
to a gene that encodes a DNA gyrase subunit, an enzyme involved in returning newly
replicated DNA to its supercoiled form. As a result, the antibiotic no longer binds to the
mutant enzyme.13
The mechanism of amino-lactam resistance of S. pneumoniae involves genetic mutations
that alter penicillin-binding protein structure and result in decreased affinity for all beta-
lactam antibiotics.14 This mechanism of resistance is acquired through a process known as
“natural transformation,” in which a particular genome encoding the alteration is picked
up from other pneumococci and incorporated into their own DNA. Bacteria, single-celled
organisms, often donate antibiotic-resistant genes to other species of bacteria in the human
body. There are three common forms of horizontal gene transfer: transduction, conjugation
and transformation. Horizontal gene transfer is distinguished from vertical transfer, which
occurs between a parent and its offspring. Horizontal gene transfers are fairly common in
nature and may have contributed to the genetic diversity now evident in bacteria.15
The ability of pneumococcal strains to acquire resistance from a wide variety of organ-
isms is particularly disturbing, given the prevalence of enterococci bacteria that carry a
transferable gene for vancomycin resistance. Resistance to vancomycin occurs when several
genes encode several proteins that comprise a pathway for changing the peptidoglycan,
cross-linking peptides into a form that no longer binds vancomycin but can still be cross-
linked by bacterial enzymes.16 MRSA and vancomycin-resistant enterococci (VRE) cause
nosocomial infections and are associated with increased rates of illness and death. Both
organisms are now endemic in many institutions, particularly in intensive care units.17
Bacterial Strategies
Bacteria use several strategies to combat antibiotics. First, they can produce specific pro-
teins that chemically modify the antibiotic to prevent the drug from interfering with the
activity that it was designed to inhibit. Second, bacteria can insert a protein or efflux pump
into their cytoplasmic membranes. This pump can eject the antibiotic as soon as the antibi-
otic moves into the cytoplasm. As a result, the concentration of the antibiotic in the vicinity
of the bacterial ribosomes is too low to effectively inhibit the synthesis of bacterial proteins.
An Overview of Antibiotic Resistance
tuberculosis and gonorrhea, the fungi that cause yeast infections and the parasites that
cause malaria, are becoming resistant to standard therapies.
The Mechanism of Resistance
Research efforts previously directed toward discovering new antibiotics are now largely
focused on learning the mechanics of bacterial resistance. Bacteria have developed two
types of strategies for circumventing the action of antibiotics: 1) by mutation where
an alteration in a gene produces a change in later generations or 2) by incorporating
exogenous genetic material as described previously in the first reported VRSA case in
Michigan.11 The end result is a decreased or complete lack of susceptibility of the organisms
to antibiotics that were previously effective. While some bacteria have intrinsic resistance
mechanisms that predate the introduction of antibiotics, others have developed resistance
due to many contributing factors, such as overuse, suboptimal dosing, incorrect choice of
antibiotic, incorrect duration of treatment or inappropriate route of administration.
Understanding the mechanisms and effects of mutation can be quite complicated. For
example, fluoroquinolone resistance, in part, “arises from spontaneous mutations in the
genes encoding the enzyme subunits. With GyrA and ParC units of the resistant bacteria,
amino acid changes are generally localized to a region of the enzyme in the amino termi-
nus that contains the active site, a tyrosine that is covalently linked to the broken DNA
strand during enzyme action. For the GyrB and ParE subunits of resistant bacteria, amino
acid changes, when present, are usually localized to the midportion of the subunit in a
domain involved in interactions with their complementary subunits.”12 In simpler terms,
bacteria can become resistant to fluoroquinolones by making one or a few mutations
to a gene that encodes a DNA gyrase subunit, an enzyme involved in returning newly
replicated DNA to its supercoiled form. As a result, the antibiotic no longer binds to the
mutant enzyme.13
The mechanism of amino-lactam resistance of S. pneumoniae involves genetic mutations
that alter penicillin-binding protein structure and result in decreased affinity for all beta-
lactam antibiotics.14 This mechanism of resistance is acquired through a process known as
“natural transformation,” in which a particular genome encoding the alteration is picked
up from other pneumococci and incorporated into their own DNA. Bacteria, single-celled
organisms, often donate antibiotic-resistant genes to other species of bacteria in the human
body. There are three common forms of horizontal gene transfer: transduction, conjugation
and transformation. Horizontal gene transfer is distinguished from vertical transfer, which
occurs between a parent and its offspring. Horizontal gene transfers are fairly common in
nature and may have contributed to the genetic diversity now evident in bacteria.15
The ability of pneumococcal strains to acquire resistance from a wide variety of organ-
isms is particularly disturbing, given the prevalence of enterococci bacteria that carry a
transferable gene for vancomycin resistance. Resistance to vancomycin occurs when several
genes encode several proteins that comprise a pathway for changing the peptidoglycan,
cross-linking peptides into a form that no longer binds vancomycin but can still be cross-
linked by bacterial enzymes.16 MRSA and vancomycin-resistant enterococci (VRE) cause
nosocomial infections and are associated with increased rates of illness and death. Both
organisms are now endemic in many institutions, particularly in intensive care units.17
Bacterial Strategies
Bacteria use several strategies to combat antibiotics. First, they can produce specific pro-
teins that chemically modify the antibiotic to prevent the drug from interfering with the
activity that it was designed to inhibit. Second, bacteria can insert a protein or efflux pump
into their cytoplasmic membranes. This pump can eject the antibiotic as soon as the antibi-
otic moves into the cytoplasm. As a result, the concentration of the antibiotic in the vicinity
of the bacterial ribosomes is too low to effectively inhibit the synthesis of bacterial proteins.
An Overview of Antibiotic Resistance