1、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
2、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 topica
3、l 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 topica
4、l antibiotics,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 1960s. Mupirocin wo
5、rks 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,Polymy
6、xin B,Polymixin B,Member of the lipopeptide class of antibiotics, similar to daptomycin,Daptomycin,Polymixin B,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 posi
7、tive 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 perm
8、eable.,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
9、 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 hydroly
10、sis 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 line
11、ar 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
12、use. Mechanism of action is believed to be at the cytoplasmic membrane.,Gramicidins: Mechanism of action,The gramicidins behave as ionophoric substances The gramicidins self associate, thus forming small pores that cause leakage of essential cations from the cytoplasm,A gramicidin channel,Gramicidin
13、 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. Primary structure of gramicidin (A):,HCO-L-Val-Gly-L-Ala-D-Leu-L-Ala-D-Val-L-Val-D-Val-L-Trp-D-Leu-L-Trp-D-Leu-L-Trp-D-Leu
14、-L-Trp- NHCH2CH2OH 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 gram
15、icidin channels can be observed if a small number of gramicidin molecules is present in a lipid bilayer separating 2 compartments containing salt solutions.,Neomycin,Historical: Aminoglycosides,Waksman and Schatz demonstrated the antibacterial activity of Streptomyces griseus in 1943 Streptomycin is
16、olated 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
17、 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 bacter
18、ia, 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).,
19、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 unknow
20、n, 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 c
21、ommonly 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.,
