Treatment of anthrax infection with combination of ciprofloxacin and antibodies to protective antigen of<i>Bacillus anthracis</i>

Karginov, Vladimir A.; Robinson, Tanisha M.; Riemenschneider, Jenny; Golding, Basil; Kennedy, Michael J.; Shiloach, Joseph; Alibek, Ken

doi:10.1016/s0928-8244(03)00302-x

Cited by 46 publications

(34 citation statements)

References 12 publications

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“…Although naturally occurring anthrax infection of humans is rare, the 2001 anthrax attack through the US Postal Service highlighted the need for a safe and efficacious postexposure therapy for anthrax infection. The current Centers for Disease Control recommendations for treatment following potential exposure to aerosolized B. anthracis spores calls for administration of antibiotics for at least 60 d and the licensed protective antigen-based vaccine (1). However, antibiotic treatment can be ineffective when bacterial strains are antibiotic resistant (2).…”

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confidence: 99%

Pre- and postexposure protection against virulent anthrax infection in mice by humanized monoclonal antibodies to Bacillus anthracis capsule

Chen¹,

Schneerson

Lovchik

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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One of the two essential virulence factors of Bacillus anthracis is the poly-γ-D-glutamic acid (γDPGA) capsule. Five γDPGA-specific antibody antigen-binding fragments (Fabs) were generated from immunized chimpanzees. The two selected for further study, Fabs 11D and 4C, were both converted into full-length IgG1 and IgG3 mAbs having human IgG1 or IgG3 constant regions. These two mAbs had similar binding affinities, in vitro opsonophagocytic activities, and in vivo efficacies, with the IgG1 and IgG3 subclasses reacting similarly. The mAbs bound to γDPGA specifically with estimated binding affinities (K d ) of 35-70 nM and effective affinities (effective K d ) of 0.1-0.3 nM. The LD 50 in an opsonophagocytic bactericidal assay was ≈10 ng/mL of 11D or 4C. A single 30-μg dose of either mAb given to BALB/c mice 18 h before challenge conferred about 50% protection against a lethal intratracheal spore challenge by the virulent B. anthracis Ames strain. More importantly, either mAb given 8 h or 20 h after challenge provided significant protection against lethal infection. Thus, these anti-γDPGA mAbs should be useful, alone or in combination with antitoxin mAbs, for achieving a safe and efficacious postexposure therapy for anthrax.

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confidence: 99%

Pre- and postexposure protection against virulent anthrax infection in mice by humanized monoclonal antibodies to Bacillus anthracis capsule

Chen¹,

Schneerson

Lovchik

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…If antibiotics are applied at this stage, the infection can still be lethal because of the accumulation of the toxins. Logically, an effective therapeutic approach would include simultaneous blocking of bacterial growth by antibiotics and neutralization of anthrax toxin with antitoxins (2)(3)(4)(5). Extensive research efforts both before and after the anthrax attacks of 2001 have made anthrax toxin one of the best-understood channel-facilitated protein translocation systems (refs.…”

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confidence: 99%

Blocking anthrax lethal toxin at the protective antigen channel by using structure-inspired drug design

Karginov

Nestorovich

Moayeri

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

110

160

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Bacillus anthracis secretes three polypeptides: protective antigen (PA), lethal factor (LF), and edema factor (EF), which interact at the surface of mammalian cells to form toxic complexes. LF and EF are enzymes that target substrates within the cytosol; PA provides a heptameric pore to facilitate LF and EF transport into the cytosol. Other than administration of antibiotics shortly after exposure, there is currently no approved effective treatment for inhalational anthrax. Here we demonstrate an approach to disabling the toxin: high-affinity blockage of the PA pore by a rationally designed low-molecular weight compound that prevents LF and EF entry into cells. Guided by the sevenfold symmetry and predominantly negative charge of the PA pore, we synthesized small cyclic molecules of sevenfold symmetry, ␤-cyclodextrins chemically modified to add seven positive charges. By channel reconstitution and high-resolution conductance recording, we show that per-6-(3-aminopropylthio)-␤-cyclodextrin interacts strongly with the PA pore lumen, blocking PA-induced transport at subnanomolar concentrations (in 0.1 M KCl). The compound protected RAW 264.7 mouse macrophages from cytotoxicity of anthrax lethal toxin ‫؍(‬ PA ؉ LF). More importantly, it completely protected the highly susceptible Fischer F344 rats from lethal toxin. We anticipate that this approach will serve as the basis for a structure-directed drug discovery program to find new and effective treatments for anthrax.infectious diseases ͉ membrane transport ͉ modified cyclodextrins

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“…Moreover it has been shown that the combination of toxin neutralization with antibodies and inhibition of bacterial growth by antibiotics is very effective in a small animal anthrax challenge model [14]. Antianthrax toxin antibodies, which neutralize the immunosuppressive effects of PA/LF/EF, working in concert with conventional antibiotics may provide additional protection in the event of an anthrax spore exposure.…”

Section: Introductionmentioning

confidence: 99%

Human monoclonal antibodies that neutralize anthrax toxin by inhibiting heptamer assembly

Wang

Ruther

Jiang

et al. 2005

HAB

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Human monoclonal antibodies that neutralize anthrax toxin by inhibiting heptamer assembly, pp. 105-110. Copyright © (2004), with permission from IOS Press. Available online at:http://iospress.metapress.com/openurl.asp?genre=article&issn=1093-2607&volume=13&issue=4&spage=105The Eprints service at the University of Westminster aims to make the research output of the University available to a wider audience. Copyright and Moral Rights remain with the authors and/or copyright owners. Users are permitted to download and/or print one copy for non-commercial private study or research. Further distribution and any use of material from within this archive for profitmaking enterprises or for commercial gain is strictly forbidden.Whilst further distribution of specific materials from within this archive is forbidden, you may freely distribute the URL of the University of Westminster Eprints (http://eprints.wmin.ac.uk).In case of abuse or copyright appearing without permission e-mail wattsn@wmin.ac.uk. WestminsterResearchhttp://www.wmin.ac.uk/westminsterresearchThe WestminsterResearch online digital archive at the University of Westminster aims to make the research output of the University available to a wider audience. Copyright and Moral Rights remain with the authors and/or copyright owners. Users are permitted to download and/or print one copy for non-commercial private study or research. Further distribution and any use of material from within this archive for profit-making enterprises or for commercial gain is strictly forbidden.Whilst further distribution of specific materials from within this archive is forbidden, you may freely distribute the URL of WestminsterResearch. (http://www.wmin.ac.uk/westminsterresearch). Abstract. A panel of human anti-anthrax protective antigen IgG1 monoclonal antibodies were evaluated to determine the mechanism of toxin neutralization. AVP-22G12, AVP-1C6 and AVP-21D9 bound to the protective antigen with picomolar affinities to distinct non-overlapping linear epitopes. Two of the antibodies neutralized the anthrax toxin by completely inhibiting the protective antigen oligomer assembly process in vitro.

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Treatment of anthrax infection with combination of ciprofloxacin and antibodies to protective antigen ofBacillus anthracis

Cited by 46 publications

References 12 publications

Pre- and postexposure protection against virulent anthrax infection in mice by humanized monoclonal antibodies to Bacillus anthracis capsule

Pre- and postexposure protection against virulent anthrax infection in mice by humanized monoclonal antibodies to Bacillus anthracis capsule

Blocking anthrax lethal toxin at the protective antigen channel by using structure-inspired drug design

Human monoclonal antibodies that neutralize anthrax toxin by inhibiting heptamer assembly

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