Listeria+Sp14

__ DISEASE/DRUG OF INTEREST: __ Listeria (Listeriosis)/Ampicillin

__ MOTIVATION AND BACKGROUND: __ Listeriosis is a serious infection caused by eating food contaminated with the bacterium Listeria monocytogenes [1]. It can be in a variety of raw foods as well as in processed foods and foods made from unpasteurized milk. Listeria is unlike many other germs because it can grow even in the cold temperature of the refrigerator [2]. Symptoms include fever and chills, headache, upset stomach and vomiting [2]. In infants, symptoms of Listeriosis may be seen in the first few days of life and may include loss of appetite, lethargy, jaundice, respiratory distress (usually pneumonia), shock, skin rash, vomiting [3]. If you eat the contaminated products, you may get sick. The following people are at increased risk: Adults over age 50, adults with a weakened immune system, developing fetuses, newborns, pregnant women[3]. The disease can manifest as septicemia, meningitis or meningoencephalitis; or result in stillbirth or abortion in pregnant women [4]. Nationwide, 1,651 cases of listeriosis occurring during 2009-2011 were reported. The case-fatality rate was 21%. Most cases occurred among adults aged ≥65 years (950 [58%]), and 14% (227) were pregnancy-associated. At least 74% of nonpregnant patients aged <65 years had an immunocompromising condition, most commonly immunosuppressive therapy or malignancy. The average annual incidence was 0.29 cases per 100,000 population. Compared with the overall population, incidence was markedly higher among adults aged ≥65 years (1.3; relative rate [RR]: 4.4) and pregnant women (3.0; RR: 10.1). Twelve reported outbreaks affected 224 patients in 38 states. Five outbreak investigations implicated soft cheeses made from pasteurized milk that were likely contaminated during cheese-making (four implicated Mexican-style cheese, and one implicated two other types of cheese). Two outbreaks were linked to raw produce [5].

__ TARGET INFORMATION: __ The specific target protein that this bacterium interacts with is really hard to find so the following may be not so accurate, but I found that the bacterial protein InlC is able to link to the sixth SH3 domain (SH3-6) of human Tuba [6]. I was able to find the size of full length Tuba to be about 180K [7]. Listeria can attach to and enter mammalian cells [8]. There is also another type of attachment of this bacterium within a human. The bacterium is thought to attach to epithelial cells of the GI tract by means of D-galactose residues on the bacterial surface, which adhere to D-galactose receptors on the host cells [8]. If this is correct, it is the opposite of the way that most other bacterial pathogens are known to adhere, i.e., the bacterium displays the protein or carbohydrate ligand on its surface and the host displays the amino acid or sugar residue to which the ligand binds [8]. Having said this, macrophages are well known to have "mannose binding receptors" on their surface whose function presumably is to ligand to bacterial surface polysaccharides that terminate in mannose, as a prelude to phagocytic uptake [8].



Figure 4. Steps in the invasion of cells and intracellular spread by L. monocytogenes. The bacterium apparently invades via the intestinal mucosa. It is thought to attach to intestinal cells by means of D- galactose residues on the bacterial surface which adhere to D-galactose receptors on susceptible intestinal cells The bacterium is taken up (including by non phagocytic cells) by induced phagocytosis, which is thought to be mediated by a membrane associated protein called internalin. Once ingested the bacterium produces listeriolysin (LLO) to escape from the phagosome. The bacterium then multiplies rapidly in the cytoplasm and moves through the cytoplasm to invade adjacent cells by polymerizing actin to form long tails.

__ DRUG INFORMATION: __

Ampicillin is a beta-lactam antibiotic that has been used extensively to treat bacterial infections since 1961 [9]. Until the introduction of ampicillin by the British company Beecham, penicillin therapies had only been effective against Gram-positive organisms such as staphylococci and streptococci [9]. Ampicillin (originally branded as 'Penbritin') also demonstrated activity against Gram-negative organisms such as H. influenzae, coliforms and Proteus spp [9]. Ampicillin was the first of a number of so-called broad spectrum penicillins subsequently introduced by Beecham [9]. Ampicillin is part of the aminopenicillin family and is roughly equivalent to its successor, amoxicillin in terms of spectrum and level of activity [9]. It can sometimes result in reactions that range in severity from a rash (in the case of patients that may unwittingly have mononucleosis) to potentially lethal allergic reactions such as anaphylaxis [9]. However, as with other penicillin drugs, it is relatively non-toxic and adverse effects of a serious nature are encountered only infrequently [9]. Belonging to the penicillin group of beta-lactam antibiotics, ampicillin is able to penetrate Gram-positive and some Gram-negative bacteria [9]. It differs from penicillin only by the presence of an amino group [9]. That amino group helps the drug penetrate the outer membrane of gram-negative bacteria [9]. Ampicillin acts as a competitive inhibitor of the enzyme transpeptidase, which is needed by bacteria to make their cell walls [9]. It inhibits the third and final stage of bacterial cell wall synthesis in binary fission, which ultimately leads to cell lysis. Ampicillin has received FDA approval for its mechanism of action [9]. Ampicillin acts as a competitive inhibitor of the enzyme transpeptidase, which is needed by bacteria to make their cell walls [9]. It inhibits the third and final stage of bacterial cell wall synthesis in binary fission, which ultimately leads to cell lysis [9]. Ampicillin has received FDA approval for its mechanism of action [9]. __Formula__: C16H19N3O4S __Mol. Mass__: 349.41g*mol-1 __CAS Number__: 69534 __Delivery Method__: for ampicillin can be either oral, with pill or suspension, or injected. __Side Effects__: ampicillin affects chloroplast division. Ampicillin, like other β-lactam antibiotics, not only blocks the division of bacteria, but also the division of chloroplasts of the Glaucophytes (called cyanelles) and chloroplasts of the moss Physcomitrella patens, a bryophyte [9]. In contrast, it has no effect on the plastids of the higher developed vascular plant Lycopersicon esculentum L. (tomato) [9]. __Company or Maker__: a British company called Beecham makes ampicillin __Is it Patented?__ Yes, it is patented by more than 22838 companies. __Clinical Trial__: currently there are 44 clinical trials happening that involve ampicillin acoording to clinicaltrails.gov __Origin:__ ampicillin belongs to the penicillin group of beta-lactam antibiotics. __Alternatives__: Carbenicillin. Carbenicillin is recommended as a substitute for ampicillin at the same concentration in molecular biology applications [10]. Both ampicillin and carbenicillin are semi-synthetic penicillins related to penicillin [10]. Carbenicillin is penicillin with a carboxyl and benzyl group whereas ampicillin is an aminopenicillin [10]. Carbenicillin inhibits cell wall synthesis in peptidoglycan crosslinking because it is a member of the penicillin family of antibiotics [10]. __Other Uses__: this drug is also used to treat various infections of the urinary, respiratory, and intestinal tracts.



__ REFERENCES: __ [1]. Schlech, W. F.; Lavigne, P. M.; Bortolussi, R. A.; Allen, A. C.; Haldane, E. V.; Wort, A. J.; Hightower, A. W.; Johnson, S. E.; King, S. H.; Nicholls, E. S.; Broome, C. V., Epidemic listeriosis-- evidence for transmission by food. N Engl J Med 1983, 308 (4), 203-6.

[2]. Baltimore RS. Listeria monocytogenes. In: Kliegman RM, Behrman RE, Jenson HB, Stanton BF, eds. Nelson Textbook of Pediatrics. 19th ed. Philadelphia, Pa: Saunders Elsevier; 2011:chap 181. [3]. Bennett L. Listeria monocytogenes. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases. 7th ed. Philadelphia, Pa: Elsevier Churchill Livingstone; 2009:chap 207. [4]. Klumpp, J.; Loessner, M. J., Listeria phages: Genomes, evolution, and application. Bacteriophage 2013, 3 (3), e26861.

[5]. (CDC), C. f. D. C. a. P., Vital signs: Listeria illnesses, deaths, and outbreaks--United States, 2009- 2011. MMWR Morb Mortal Wkly Rep 2013, 62 (22), 448-52.

[6]. Polle, L.; Rigano, L. A.; Julian, R.; Ireton, K.; Schubert, W. D., Structural Details of Human Tuba Recruitment by InlC of Listeria monocytogenes Elucidate Bacterial Cell-Cell Spreading. Structure 2013. [7]. Rajabian, T.; Gavicherla, B.; Heisig, M.; M�ller-Altrock, S.; Goebel, W.; Gray-Owen, S. D.; Ireton, K., The bacterial virulence factor InlC perturbs apical cell junctions and promotes cell-to-cell spread of Listeria. Nat Cell Biol 2009, 11 (10), 1212-8.

[8]. Textbook of Bacteriology. The Microbial World: Listeria and Listeriosis. http://textbookofbacteriology.net/themicrobialworld/Listeria.html (Accessed Feb 3 2014).

[9]. Princeton University. Ampicillin. http://www.princeton.edu/~achaney/tmve/wiki100k/docs/Ampicillin.html (Accessed Feb 3 2014)

[10]. Cellgro. Ampicillin vs. Carbenicillin. http://cellgro.com/media/upload/file/productinfosheets/new/Ampicillin%20vs_%20Carbenicillin.pdf (Accessed Feb 3 1014)