Bacterial anthrax

Anthrax Bacterial agent that may cause inhalation anthrax, cutaneous anthrax, or gastrointestinal anthrax disease. 

Slow-acting, noncontagious biological agents. These agents, which include viruses as well as the bacterial causative agents for anthrax and tularemia, produce no initial symptoms, but cause flu-like symptoms after a... 

Bacterial agents, such as Bacillus anthracis (the causative agent for anthrax), or Yersinia pestis (the causative agent for plague). 

Events involving deliberate or accidental distribution of bacterial pathogens into our everyday environment have clearly defined the need for a sensitive, specific, and rapid method of bacterial detection. Bioterrorism was first introduced in the United States in 1984 with the Salmonella typhimurium attack in The Dalles, Oregon, by a cult group attempting to affect a local election.1 As a result of this act 751 people contracted salmonellosis, which totally overwhelmed the hospitals and medical clinics with patients. Later our society became keenly aware of the potential of bioterrorism during the last four months of 2001 when Bacillus anthracis (anthrax) spores were sent through the US mail in an envelope to several locations. These events had... 

The anthrax bioterrorist attacks that followed the events of September 11th 2001 resulted in a renewed interest BadUus anthracis, the causative agent of this disease. Research has focused on the development of better vaccines than the one currently available. It has been estimated that the aerosolized release of 100 kg of anthrax spores upwind of Washington DC would cause mortalities of 130,000-3,000,000 [63]. Nonetheless, wild-type Bacillus anthracis is susceptible to conventional antibiotics, including penicillin, oxyfloxacin and ciprofloxacin. The problem lies not with the bacterial infection itself, but with three proteins released by the bacteria - protective antigen (PA, 83 kDa), lethal factor (LF, 90 kDa) and edema factor (EF, 89 kDa) -known as anthrax toxins [63]. 

Ciprofloxacin An antibiotic drug useful in treating bacterial infections the recommended antibiotic for treating anthrax infections as well as prophylaxis in a biological warfare setting. 

Classical bacterial exotoxins, such as diphtheria toxin, cholera toxin, clostridial neurotoxins, and the anthrax toxins are enzymes that modify their substrates within the cytosol of mammalian cells. To reach the cytosol, these toxins must first bind to different cell-surface receptors and become subsequently internalized by the cells. To this end, many bacterial exotoxins contain two functionally different domains. The binding (B-) domain binds to a cellular receptor and mediates uptake of the enzymatically active (A-) domain into the cytosol, where the A-domain modifies its specific substrate (see Figure 1). Thus, three important properties characterize the mode of action for any AB-type toxin selectivity, specificity, and potency. Because of their selectivity toward certain cell types and their specificity for cellular substrate molecules, most of the individual exotoxins are associated with a distinct disease. Because of their enzymatic nature, placement of very few A-domain molecules in the cytosol will normally cause a cytopathic effect. Therefore, bacterial AB-type exotoxins which include the potent neurotoxins from Clostridium tetani and C. botulinum are the most toxic substances known today. However, the individual AB-type toxins can greatly vary in terms of subunit composition and enzyme activity (see Table 2). 

Anthrax toxin is a bacterial toxin from Bacillus anthracis consisting of three parts protective antigen (PA), lethal factor (LF) and edema factor (EF). Both LF and EF compete for binding sites on the PA protein. The PA protein binds with high affinity to an as yet unknown receptor on macrophages and related cell types. When PA is internalized by the target cells, it functions as a shuttle protein for either EF or LF. Intracellularly, in the acidic environment of the endosome, EF and LF are capable of entering the cytosol by pH-dependent pore formation [139]. 

Levofloxacin (1), the levo-isomer or the (5)-enantiomer of ofloxacin, received FDA approval in 1996 (Fish, 2003 Hurst et al., 2002 Mascaretti, 2003 Norrby, 1999 North et al., 1998). The initial approval covered community-acquired pneumonia, acute bacterial exacerbation of chronic bronchitis, acute maxillary sinusitis, uncomplicated skin and skin structure infections, acute pyelonephritis, and complicated urinary tract infections (North et al., 1998). Four years later, the levofloxacin indication list grew to include community-acquired pneumonia caused by penicillin-resistant Streptococcus pneumoniae. In addition, in 2002, nosocomial (hospital-acquired) pneumonia caused by methicillin-susceptible Staphylococcus aureus, Pseudomonas aeruginosa, Serratia marcescens, Haemophilus influenzae, Kliebsella pneumoniae, and Escherichia coli was added (Hurst et al., 2002). Finally in 2004, LVX was approved as a post-exposure treatment for individuals exposed to Bacillus anthracis, the microbe that causes anthrax, via inhalation (FDA, 2004). 

The fluoroquinolone subclass of antibiotics is inspired by nalidixic acid (A.35), an older antibiotic commonly used for urinary tract infections (Figure A.10). Depending on the type of infection, fluoroquinolones inhibit DNA gyrase and/or topoisomerase IV. Both enzymes are vital for DNA replication and bacterial reproduction. Both ciprofloxacin (Cipro, A.36) and levofloxacin (Levaquin, A.37) are examples of fluoroquinolone antibiotics. Ciprofloxacin received national attention in the United States in 2001. Ciprofloxacin was used to treat many anthrax-infected patients after letters containing anthrax spores were sent through the U.S. postal service. 

Cethromycin (ABT-773) 39 (Advanced Life Sciences) had an NDA filed in October 2008 for the treatment of CAP.67 Advanced Life Sciences is also evaluating cethromycin 39 against other respiratory tract infections and in pre-clinical studies as a prophylactic treatment of anthrax post-exposure. Cethromycin 3968 70 is a semi-synthetic ketolide derivative of erythromycin 4071 originally synthesised by Abbott Laboratories,72 which like erythromycin 40, inhibits bacterial protein synthesis through binding to the peptidyl-transferase site of the bacterial 50S ribosomal subunit. Important macrolide antibiotics in clinical use today include erythromycin 40 itself, clarithromycin, azithromycin and, most recently, telithromycin (launched in 2001). 

Figure 1.4. Paul Ehrlich. Paul Ehrlich was a German Jewish physician and scientist, who was inspired by and initially worked with Robert Koch (who discovered the causative bacterial agents of Anthrax, Tuberculosis, and Cholera). Left Ehrlich s portrait on a 200 deutschmarks bill (now obsolete).

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