Transcript Topical Antibiotics

Topical Antibiotics
• Topical antibiotics help prevent infections caused by
bacteria that get into minor cuts, scrapes, and burns.
• Treating minor wounds with antibiotics allows quicker
healing.
• If the wounds are left untreated, the bacteria will
multiply, causing pain, redness, swelling, itching, and
oozing.
• Untreated infections can eventually spread and
become much more serious.
Which bacteria?
• Most topical antibiotics are directed against
Staphylococcus aureus and Streptococcus
pyogenes.
• The anaerobic Gram-positive bacterial
species Propionibacterium acnes has been
linked to acne.
Which topical antibiotics are
common?
• Some widely used topical antibiotics are
bacitracin, neomycin, mupirocin, and
polymyxin B.
• Among the products that contain one or
more of these ingredients are Bactroban
(a prescription item), Neosporin,
Polysporin, and Triple Antibiotic Ointment
or Cream.
Classes of topical antibiotics
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Cell wall synthesis inhibitors
Ribosome function inhibitors
Sulfa drugs
Burn treatment agents
Miscellaneous
Mupirocin (90% Pseudomonic acid A)
• Isolated from Pseudomonas fluorescens
– Antibacterial activity of substance from P. fluorescens
noted in 1887
– Purified in the 1960’s.
• Mupirocin works against Gram-positive bacteria
only
• Can be used to treat MRSA (although resistance is
rising)
• Ester linkage is rapidly hydrolyzed
hepatically, thus precluding utility as an
oral or intravenous antibiotic
• Mupirocin inhibits bacterial isoleucyl-tRNA
synthetase.
Products containing Mupirocin
Polymyxin B
Polymixin B
Daptomycin
Polymixin B
• Member of the lipopeptide class of
antibiotics, similar to daptomycin
Polymyxin: Antibacterial activity
• However, the polymyxins are only active
against gram negative bacteria (P.
aeruginosa, E. coli, K. pneumoniae), while
daptomycin is used to treat gram positive
bacteria
• The polymyxins are highly nephrotoxic and
are thus only used topically
Polymyxins: Mechanism of action
• Bind the the lipopolysaccharide in the outer
membrane, thus destroying OM integrity.
• Bind to the cytoplasmic membrane (to the
phosphatidylethanolamine) and make the
membrane more permeable.
Products containing polymyxin B
Bacitracin A
Bacitracin: History
• Isolated by John T. Goorley in 1943
• Found in the infected compound
fracture of the patient Margaret Tracy
Bacitracin: Antibacterial
Activity
• Primarily used against gram positive
bacteria S. aureus and Streptococci
spp.
• Most gram negative organisms are
resistant
Bacitracin: Mechanism
• Bacitracin interferes with bacterial cell wall
synthesis
• Acts by blocking a step in the process
whereby the key subunits are transferred
from the cytoplasm
• Specifically bacitracin tightly binds
undecaprenyl pyrophosphate, preventing the
hydrolysis into undecaprenyl phosphate
• This step is essential for recycling of the
carrier
• Link
Products containing Bacitracin
Gramicidin
Gramicidin S
Gramicidins
• The Gramicidins are small
peptides (15 amino acids)
• Some, such as gramicidin S, are
cyclic
• Others, including Gramicidin A,
B, C, and D, are linear
• Commercial gramicidin is a
mixture of compounds, with
gramicidin A being major
Gramicidins
• Gramicidin S is a powerful antibacterial
agent, with broad range against a
number of Gram positive and Gram
negative microorganisms.
• Unfortunately, Gramicidin S is
hemolytic, and thus is limited to topical
use.
• Mechanism of action is believed to be at
the cytoplasmic membrane.
Gramicidins: Mechanism of action
A gramicidin channel
• The gramicidins behave as ionophoric
substances
• The gramicidins self associate, thus
forming small pores that cause leakage
of essential cations from the cytoplasm
Gramicidin is an unusual peptide,
with alternating D & L amino acids.
In lipid bilayer membranes,
gramicidin dimerizes & folds as a
right-handed b-helix.
The dimer just spans the bilayer.
Gramicidin dimer
(PDB file 1MAG)
Primary structure of gramicidin
(A):
HCO-L-Val-Gly-L-Ala-D-Leu-L-Ala-D-Val-L-Val-D-ValL-Trp-D-Leu-L-Trp-D-Leu-L-Trp-D-Leu-L-TrpNHCH2CH2OH
Note: The amino acids are all
hydrophobic; both peptide ends are modified (blocked).
The outer surface of the
gramicidin dimer, which
interacts with the core of the
lipid bilayer, is hydrophobic.
Ions pass through the more
polar lumen of the helix.
Ion flow through individual
gramicidin channels can be
observed if a small number of
gramicidin molecules is
present in a lipid bilayer
separating 2 compartments
containing salt solutions.
Gramicidin dimer
(PDB file 1MAG)
Neomycin
Historical: Aminoglycosides
• Waksman and Schatz demonstrated the
antibacterial activity of Streptomyces griseus
in 1943
• Streptomycin isolated in 1944
• Neomycin isolated from Streptomyces
fradiae in 1949
Neomycin
• Neomycin is extremely nephrotoxic, thus
limiting its use to a topical antibiotic
• Neomycin has excellent activity against
gram negative bacteria and partial activity
against gram positive strains
• Some people have allergies to neomycin
• Like other aminoglycosides, neomycin works
by binding to the bacterial 30S ribosomal
subunit, thus inhibiting protein synthesis.
Silver sulfadiazine
• Sulfa drug works by normal mechanism of
interfering with the biosynthesis of folic acid
• Heavy metals, like silver, seem to be toxic to
bacteria, probably due to their ability to denature
proteins through reaction with disulfide bonds
Uses
• Used to treat burn patients
Treatment of Acne Vulgaris
What Causes Acne?
• Acne is a result of clogging of a hair follicle,
and simultaneous activation of the sebaceous
gland (thus producing more sebum).
• A commensal bacterium, Propionibacterium
acnes, which lives on the skin, but is also
present in the follicle, causes inflammation
and thus contributes to the problem.
Propionibacterium acnes
• Killing the bacteria can help with treatment
of acne
Benzoyl Peroxide
• Exact antibacterial mechanism is unknown,
but presumably involves oxidation of
essential bacterial structures.
Clindamycin
The antibiotic clindamycin is commonly
used topically in the treatment of acne
• Recall that clindamycin is a member of the
lincosamide class of antibacterial agents and
acts at the bacterial ribosome.
• Clindamycin is commonly used to treat
aerobic Gram-positive bacteria.
Assigned Reading
• Noah Scheinfeld A primer on topical
antibiotics for the skin and eyes.
Journal of drugs in dermatology : JDD
(2008), 7(4), 409-15.
Homework Question
• List the primary target organism and the
mechanism of action of the topical
antibiotics discussed in this
presentation.