Q+Fever

=__**Disease/Drug of interest** : __Q fever and doxycycline =

Q fever, a zoonotic disease caused by the intracellular, gram-negative bacterium //Coxiella burnetii,// is ranked by the National Institute of Allergy and Infectious Diseases (NIAID) as a Category B agent of bioterrorism as it has the potential to cause incapacitating disease across masses of people (Fig.1) [1,2]. The disease was investigated during the Cold War for its use in biological warfare, and the Soviet Union reportedly mass-produced //C. burnetti //to be used as a biological weapon [3].

In nature, //C. burnetti// often infect sheep and cattle, and humans become infected through inhalation of contaminated dusts from such animals (Fig. 2). People in close contact with animals (famers,veterinarians) as well as scientists who work with infected animals have the highest risk of becoming infected [1]. //C. burnetti// can be spread through aerosols, and since the bacteria are largely resistant to heat and chemicals, they can survive in the environment for extended periods of time. Additionally, a single bacterium can cause clinical infection in 50% of a population (ID50=1) [4]. Thus, studies suggest that when used against a civilian population, the infectivity rate of Q fever would be equivalent to that of anthrax [3]. Although the side effects of Q fever are rarely fatal and many cases are asymptomatic, the acute form presents as high fever, myocarditis, nausea, hepatitis, and pneumonia [5]. The chronic form, which can appear weeks to years after the initial acute infection, may cause endocarditis, aortic aneurysms, and spontaneous abortions in pregnant women. Currently, there is not an accepted vaccine against Q fever available in the United Stated nor is there a treatment for the chronic form, but the acute form can be treated with the antibiotic doxycycline [3].

 __Figure 1 __: Consequences of release of 50kg of //C. burnetti// along a 2km line upwind of a city of 500,000 people. The bacteria would spread to areas greater than 20km apart and would cause  incapacitation in 125,000 people. There would be an uncertain number of psychiatric-related disorders, 150 deaths, and 9000 people would become chronically ill [3].

 __Figure 2 __: Natural and bioterrorist modes of transmission of //Coxiella burnetti// leading to acute  disease and/or chronic disease [3]. __**Target Information** : __//<span style="color: #403838; font-family: 'Times New Roman',serif; font-size: 12pt;">C. burnetti //<span style="color: #403838; font-family: 'Times New Roman',serif; font-size: 12pt;"> exclusively target macrophages in the lungs and attach to such cells with ankyrin and then enter through phagocytosis [1]. The virulent form of the bacteria follow a nonmicrobicidal path and fuse with a lysosome <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">to form an acidic phagolysosome where they survive and multiply. Ultimately, the host cell ruptures because of uncontrolled bacterial growth, and other cells become infected [6]. <span style="color: #403838; font-family: 'Times New Roman',serif; font-size: 12pt;">The primary target for the treatment of Q fever is the bacterial 30S ribosomal subunit because the bacteria die when they can no longer produce proteins [7].


 * Size ** : <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">The 30S subunit weighs 850 kilodaltons [7].


 * Location ** : <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">The 30S subunit is part of the 70S ribosome and is located in the cytoplasm of bacterial cells [8].


 * Function in a normal cell ** : <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">In a bacterial cell, the 30S has a necessary role in protein synthesis, decoding mRNA at the E, P, and A binding sites, differentiating aminoacylated tRNA molecules, monitoring codon and anti-codon base-pairing interactions, and translating mRNA and tRNA [7,8].

__**Drug Information**** : **__<span style="font-family: 'Times New Roman',serif; font-size: 12pt;">Doxycycline binds to the 30S ribosomal subunit of bacteria and blocks the binding of aminoacyl tRNA to the A site on the ribosome which inhibits protein synthesis and leads to death (and inhibition of growth) of the bacteria [8]. Resistance to the antibiotic can come about by bacterial acquisition of new genes that code for proteins that protect ribosomes from doxycycline action [9].


 * Schematic figure of drug ** :

__<span style="font-family: 'Times New Roman',serif; font-size: 12pt;">Figure 3 __<span style="font-family: 'Times New Roman',serif; font-size: 12pt;">: Schematic 3D figure of doxycycline with carbons shown <span style="font-family: 'Times New Roman',serif; font-size: 12pt;"> in grey, nitrogens in blue, and oxygens in red [11].


 * Formula ** : C <span style="background-color: #ffffff; font-family: TimesNewRomanPS; font-size: 7pt; vertical-align: -1pt;">22 H <span style="background-color: #ffffff; font-family: TimesNewRomanPS; font-size: 7pt; vertical-align: -1pt;">24 N <span style="background-color: #ffffff; font-family: TimesNewRomanPS; font-size: 7pt; vertical-align: -1pt;">2 O <span style="background-color: #ffffff; font-family: TimesNewRomanPS; font-size: 7pt; vertical-align: -1pt;">8 <span style="font-family: 'Times New Roman',serif; font-size: 12pt; line-height: 1.5;">[10]


 * Molecular weight ** : <span style="color: #403838; font-family: 'Times New Roman',serif; font-size: 12pt;">444.435g/mol [10]

**CAS Number**: <span style="color: #2f2f2f; font-family: 'Times New Roman',serif; font-size: 12pt;">564-25-0 [10]


 * Delivery method ** : <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">Doxycyline is most commonly administered orally in pill form [11].


 * Side effects ** : <span style="color: #403838; font-family: 'Times New Roman',serif; font-size: 12pt;">Side effects of doxycycline are often minimal but may include: nausea, dizziness, loss of appetite, diarrhea, rash, and an increased risk of sunburn [5].The antibiotic is not recommended for young children or pregnant women as it may cause permanent staining of teeth.

<span style="color: #303030; font-family: 'Times New Roman',serif; font-size: 12pt;">2-Naphthacenecarboxamide, 4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo- (6CI,8CI).
 * Other names ** : <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">Doxycycline is often referred to by its brand names such as Doryx, Oracea, Monodox, Atridox, Morgidox, and more [11]. It is also known as


 * Maker or company ** : <span style="color: #242424; font-family: 'Times New Roman',serif; font-size: 12pt;">Doxycycline was originally produced by Pfizer, but it is now manufactured by many companies such as <span style="color: #222222; font-family: 'Times New Roman',serif; font-size: 12pt;">Doryx, Oracea, Monodox, Atridox, and Morgidox [11].


 * Is it patented ** ? <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">Doxycycline was formerly patented by Pfizer, but the patent expired and was not renewed [11].


 * Clinical Trials Info ** : <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">One completed clinical trial and one recruiting trial have involved the combination of Doxycycline and Q fever [12].


 * Origin ** : <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">Terramycin, a natural compound, was discovered by scientists at Pfizer through bioprospecting and was modified to become tetracycline, the first semi-synthetic antibiotic [11]. In the 1960s, Charlie Stephens, a Pfizer scientist, worked on modifying tetracycline and eventually created the doxycycline antibiotic.


 * Alternatives to this drug ** : <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">Co-trimoxazole is the recommended alternate treatment for mild cases in children under 8 years old, but treatment should be switched to doxycycline if the illness becomes more severe [5]. Doxycycline <span style="color: #403838; font-family: 'Times New Roman',serif; font-size: 12pt;">is effective at treating Q fever in adult patients and severely ill children, but co-trimoxazole has been used successfully to treat pregnant patients as well as patients who were allergic to doxycycline [13]. In addition, fluoroquinolones, which enter the cerebrospinal fluid, are recommended for patients with Q fever meningoencephalitis.


 * Miscellaneous ** : //<span style="font-family: 'Times New Roman',serif; font-size: 12pt;">C. burnetti //<span style="font-family: 'Times New Roman',serif; font-size: 12pt;">, unlike other bacteria, rely on the harshly acidic environment of the phagolysosome (pH of 4.5) to protect them from antibiotics which are less efficient in environments with lower pH levels [1, 14]. Thus, research indicates this may be the reason why patients with Qfever often relapse in spite of antibiotic treatment [13].However, the understanding of the bacteria’s dependence on an acidic environment allows for a more efficient drug coupling to target the pathogen. Doxycycline has been combined with Chloroquine, a basic agent that alkalinizes the phagolysosome, to successfully increase microbicidal, or antibacterial, activity in the phagolysosome [14].


 * Other uses ** : <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">Doxycycline has been successfully used to treat many bacterial and protozoan infections which include: Lyme disease, Rocky Mountain spotted fever, malaria, syphilis, chlamydia, bacterial pneumonia, and more.

**References:**
<span style="font-family: 'Times New Roman',serif;">1.Raoult, D.; Marrie, T.; Mege, J., Natural history and pathophysiology of Q fever. //Lancet Infect Dis// **2005,** //5// (4),219-26. <span style="font-family: 'Times New Roman',serif;">2.NIAID Emerging Infectious Diseases/Pathogens, 2016. National Institute of Allergy and Infectious Diseases (NIAID). [|https://www.niaid.nih.gov/topics/biodefenserelated/biodefense/pages/cata.aspx] (accessed Jan 29,2016). <span style="font-family: 'Times New Roman',serif;">3.Madariaga, M. G.; Rezai, K.; Trenholme, G. M.; Weinstein, R. A., Q fever: a biological weapon in your backyard. //Lancet Infect Dis// **2003,** //3// (11), 709-21. <span style="font-family: 'Times New Roman',serif;">4.Mackay, I. //Real-Time PCR in Microbiology: From Diagnosis to Characterization,// 1st ed.;Caister Academic Press, 2007; p 337. <span style="font-family: 'Times New Roman',serif;">5.Q fever: Symptoms, Diagnosis, and Treatment, 2013. Centers for Disease Control and Prevention. [|http://www.cdc.gov/qfever/symptoms/index.html] (accessed Jan 30,2016). <span style="font-family: 'Times New Roman',serif;">6.Angelakis, E.; Raoult, D., Q Fever. Vet Microbiol 2010, 140 (3-4),297-309. <span style="font-family: 'Times New Roman',serif;">7.Yonath, A., The search and its outcome: high-resolution structures of ribosomal particles from mesophilic, thermophilic, and halophilic bacteria at various functional states.//Annu Rev Biophys Biomol Struct// **2002,** //31//,257-73. <span style="font-family: 'Times New Roman',serif;">8.Wimberly, B. T.; Brodersen, D. E.; Clemons, W. M.; Morgan-Warren, R. J.; Carter, A. P.; Vonrhein, C.; Hartsch, T.; Ramakrishnan, V., Structure of the 30S ribosomal subunit.Nature 2000, 407 (6802),327-39. <span style="font-family: 'Times New Roman',serif;">9.Chopra, I.; Roberts, M., Tetracycline antibiotics: mode of action, applications, molecular biology, and epidemiology of bacterial resistance. //Microbiol Mol Biol Rev// **2001,** //65// (2), 232-60 ; second page, table ofcontents. <span style="font-family: 'Times New Roman',serif;">10.Scifinder Substance Identifier, 2016. Scifinder. https://scifinder.cas.org/scifinder/view/scifinder/scifinderExplore.jsf (accessed Jan 31,2016). <span style="font-family: 'Times New Roman',serif; line-height: 1.5;">11.PubChem.Doxycycline.[] (accessed Jan 31, 2016). <span style="font-family: 'Times New Roman',serif;">12.Clinical Trials, Search for Q fever, Doxycycline. [] (accessed Jan 30, 2016) <span style="font-family: 'Times New Roman',serif;">13.Mege, J. L.; Maurin, M.; Capo, C.; Raoult, D., Coxiella burnetii: the 'query' fever bacterium.A model of immune subversion by a strictly intracellular microorganism. //FEMSMicrobiol// //<span style="font-family: 'Times New Roman',serif;">Rev //**<span style="font-family: 'Times New Roman',serif;">1997, **//<span style="font-family: 'Times New Roman',serif;">19 //<span style="font-family: 'Times New Roman',serif;">(4),209-17 <span style="font-family: 'Times New Roman',serif;"> <span style="font-family: 'Times New Roman',serif; line-height: 1.5;">14.Maurin, M.; Benoliel, A. M.; Bongrand, P.; Raoult, D., Phagolysosomal alkalinization and the bactericidal effect of antibiotics: the Coxiella burnetii paradigm. //<span style="font-family: 'Times New Roman',serif; line-height: 1.5;">J Infect Dis // **<span style="font-family: 'Times New Roman',serif; line-height: 1.5;">1992, ** //<span style="font-family: 'Times New Roman',serif; line-height: 1.5;">166 //<span style="font-family: 'Times New Roman',serif; line-height: 1.5;">(5), 1097-102.

External links:
<span style="font-family: 'Times New Roman',serif;">https://www.niaid.nih.gov/topics/biodefenserelated/biodefense/pages/cata.aspx <span style="font-family: 'Times New Roman',serif;"> http://www.cdc.gov/qfever/symptoms/index.html <span style="font-family: 'Times New Roman',serif;">http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=54671203