CHAPTER 71 – DRUGS THAT WEAKEN THE BACTERIAL CELL WALL I: PENICILLINS
INTRODUCTION TO THE PENICILLINS
ideal antibiotic because they are active against a variety of bacteria and their direct
toxicity is low
allergic reaction is the most common adverse effect
widely prescribed for their safety and efficacy
known as beta lactam antibiotics because they have a beta lactam ring in their
structure
beta lactam family includes penicillins, cephalosporins, carbapenems, and aztreonam
Lactam antibiotics all disrupt the bacterial cell wall
mechanism of action
the bacterial cell wall is rigid permeable mesh like structure outside the cytoplasmic
membrane
inside the cytoplasmic membrane osmotic pressure is high; so if it weren't for the
rigid cell wall which prevents expansion, the bacteria would absorb water, swell, and
burst
penicillins weaken the cell wall causing bacteria to absorb water and rupture;
therefore penicillins are typically bactericidal
penicillins weaken the cell wall by (1) inhibition of transpeptidases and (2)
dysinhibition (activation) of autolysins
Trans peptidases are enzymes essential for cell wall synthesis; they catalyze the
formation of cross bridges between peptidoglycan polymer strands that form the cell
wall giving it its strength
Autolysins are bacterial enzymes that cleave bonds in the cell wall; bacteria use
these enzymes to break down the cell wall which allows growth and division
Penicillins inhibit transpeptidases and activate autolysins which disrupts synthesis of
the cell wall and promotes its active destruction
Important note, penicillins are active only against bacteria that undergo growth and
division
penicillin binding proteins (PBPs) are the molecular targets of penicillins
(transpeptidases, autolysins, and other bacterial enzymes)
Penicillins must bind to PBP's to produce antibacterial effect
PBP's are on the outer surface of the cytoplasmic membrane
of the 8 PBPs, PBP1 and PBP3 are critical to penicillins antibacterial effect
Bacteria express PBP only during growth and division therefore penicillins only work
when bacteria are growing
mammalian cells lack a cell wall so because penicillins act on enzymes that affect cell
wall integrity, the penicillins have no direct effects on host cells making them one of
the safest antibiotics
mechanisms of bacterial resistance
resistance is determined by
inability of penicillins to reach their target PBPs
inactivation of penicillins by bacterial enzymes
production of PBP's that have a low affinity for penicillins
, gram negative cell envelope
All bacteria have a cell envelope
the cell envelope of gram negative organisms differs from gram positive making
some penicillins ineffective against gram negative
Gram positive bacteria has only two layer cell envelope - the cytoplasmic membrane
and a thick cell wall; the cell wall can be penetrated easily by penicillin giving them
easy access to PBP's on the cytoplasmic membrane
Gram negative bacteria has a three layer cell envelope - the cytoplasmic membrane,
a thin cell wall, and an additional outer membrane; the cell wall can be penetrated
easily by penicillin however the outer membrane is difficult to penetrate resulting in
only certain penicillins like ampicillin to cross it to reach PBP's on the cytoplasmic
membrane
Penicillinases (B-lactamases)
B-lactamases are enzymes that cleave the B-lactam ring which inactivates penicillins
and other B-lactam antibiotics
bacteria produce a large variety of beta lactamase uses some specific for penicillins,
some specific for other single beta lactam antibiotics, and some that act on several
kinds of beta lactam antibiotics
penicillinases are B-lactamases that act selectively on penicillins
penicillin aces are synthesized by gram positive and gram negative bacteria
gram positive organisms produce large amounts of beta lactamases and export them
into the surrounding environment
gram negative organisms produce small amounts of penicillinases and secrete them
into the periplasmic space
the genes that code for beta lactamases are located on chromosomes and plasmids
(extrachromosomal DNA); genes on plasmids can be transferred from 1 bacterium to
another thus promoting the spread of penicillin resistance
penicillin resistance has become especially important with Staphylococcus aureus;
from first treatment in the 1940s by 1960 80% of staph aureus isolates in hospitals
were resistant; methicillin which is a penicillin derivative was introduced and has
resistance to the action of beta lactamase; there are still no known strains of S
aureus that produce beta lactamases capable of inactivating methicillin or related
penicillinase resistant penicillins (the are other reasons for resistance though)
altered penicillin binding proteins
o Methicillin resistant staph aureus (MRSA) has a unique mechanism of
resistance: production of PBP's with a low affinity for penicillins and other beta
lactam antibiotics
o MRSA developed this ability by acquiring genes that code for low affinity PBP's
from other bacteria
Methicillin resistant Staphylococcus aureus
Staph aureus is a gram positive bacterium that colonizes the skin and nostrils of
healthy people
infection usually involves the skin and soft tissues causing abscesses boils Cellulitis
and impetigo; serious infections can develop including in the lungs and bloodstream
which can be fatal
during the 1940s penicillin resistant strains of MRSA emerged from the bacterial
production of penicillinases
INTRODUCTION TO THE PENICILLINS
ideal antibiotic because they are active against a variety of bacteria and their direct
toxicity is low
allergic reaction is the most common adverse effect
widely prescribed for their safety and efficacy
known as beta lactam antibiotics because they have a beta lactam ring in their
structure
beta lactam family includes penicillins, cephalosporins, carbapenems, and aztreonam
Lactam antibiotics all disrupt the bacterial cell wall
mechanism of action
the bacterial cell wall is rigid permeable mesh like structure outside the cytoplasmic
membrane
inside the cytoplasmic membrane osmotic pressure is high; so if it weren't for the
rigid cell wall which prevents expansion, the bacteria would absorb water, swell, and
burst
penicillins weaken the cell wall causing bacteria to absorb water and rupture;
therefore penicillins are typically bactericidal
penicillins weaken the cell wall by (1) inhibition of transpeptidases and (2)
dysinhibition (activation) of autolysins
Trans peptidases are enzymes essential for cell wall synthesis; they catalyze the
formation of cross bridges between peptidoglycan polymer strands that form the cell
wall giving it its strength
Autolysins are bacterial enzymes that cleave bonds in the cell wall; bacteria use
these enzymes to break down the cell wall which allows growth and division
Penicillins inhibit transpeptidases and activate autolysins which disrupts synthesis of
the cell wall and promotes its active destruction
Important note, penicillins are active only against bacteria that undergo growth and
division
penicillin binding proteins (PBPs) are the molecular targets of penicillins
(transpeptidases, autolysins, and other bacterial enzymes)
Penicillins must bind to PBP's to produce antibacterial effect
PBP's are on the outer surface of the cytoplasmic membrane
of the 8 PBPs, PBP1 and PBP3 are critical to penicillins antibacterial effect
Bacteria express PBP only during growth and division therefore penicillins only work
when bacteria are growing
mammalian cells lack a cell wall so because penicillins act on enzymes that affect cell
wall integrity, the penicillins have no direct effects on host cells making them one of
the safest antibiotics
mechanisms of bacterial resistance
resistance is determined by
inability of penicillins to reach their target PBPs
inactivation of penicillins by bacterial enzymes
production of PBP's that have a low affinity for penicillins
, gram negative cell envelope
All bacteria have a cell envelope
the cell envelope of gram negative organisms differs from gram positive making
some penicillins ineffective against gram negative
Gram positive bacteria has only two layer cell envelope - the cytoplasmic membrane
and a thick cell wall; the cell wall can be penetrated easily by penicillin giving them
easy access to PBP's on the cytoplasmic membrane
Gram negative bacteria has a three layer cell envelope - the cytoplasmic membrane,
a thin cell wall, and an additional outer membrane; the cell wall can be penetrated
easily by penicillin however the outer membrane is difficult to penetrate resulting in
only certain penicillins like ampicillin to cross it to reach PBP's on the cytoplasmic
membrane
Penicillinases (B-lactamases)
B-lactamases are enzymes that cleave the B-lactam ring which inactivates penicillins
and other B-lactam antibiotics
bacteria produce a large variety of beta lactamase uses some specific for penicillins,
some specific for other single beta lactam antibiotics, and some that act on several
kinds of beta lactam antibiotics
penicillinases are B-lactamases that act selectively on penicillins
penicillin aces are synthesized by gram positive and gram negative bacteria
gram positive organisms produce large amounts of beta lactamases and export them
into the surrounding environment
gram negative organisms produce small amounts of penicillinases and secrete them
into the periplasmic space
the genes that code for beta lactamases are located on chromosomes and plasmids
(extrachromosomal DNA); genes on plasmids can be transferred from 1 bacterium to
another thus promoting the spread of penicillin resistance
penicillin resistance has become especially important with Staphylococcus aureus;
from first treatment in the 1940s by 1960 80% of staph aureus isolates in hospitals
were resistant; methicillin which is a penicillin derivative was introduced and has
resistance to the action of beta lactamase; there are still no known strains of S
aureus that produce beta lactamases capable of inactivating methicillin or related
penicillinase resistant penicillins (the are other reasons for resistance though)
altered penicillin binding proteins
o Methicillin resistant staph aureus (MRSA) has a unique mechanism of
resistance: production of PBP's with a low affinity for penicillins and other beta
lactam antibiotics
o MRSA developed this ability by acquiring genes that code for low affinity PBP's
from other bacteria
Methicillin resistant Staphylococcus aureus
Staph aureus is a gram positive bacterium that colonizes the skin and nostrils of
healthy people
infection usually involves the skin and soft tissues causing abscesses boils Cellulitis
and impetigo; serious infections can develop including in the lungs and bloodstream
which can be fatal
during the 1940s penicillin resistant strains of MRSA emerged from the bacterial
production of penicillinases
