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Teixobactin Provides Protection Against Inhalation Anthrax in the Rabbit Model

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Teixobactin Provides Protection Against Inhalation Anthrax in the Rabbit Model pathogens Article Teixobactin Provides Protection against Inhalation Anthrax in the Rabbit Model William S. Lawrence 1,2,*, Jennifer E. Peel 1 , Satheesh K. Sivasubramani 3, Wallace B. Baze 4, Elbert B. Whorton 2, David W. C. Beasley 1,5, Jason E. Comer 1,5, Dallas E. Hughes 6, Losee L. Ling 6 and Johnny W. Peterson 1,2 1 Department of Microbiology & Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA; [email protected] (J.E.P.); [email protected] (D.W.C.B.); [email protected] (J.E.C.); [email protected] (J.W.P.) 2 Institute for Human Infections & Immunity, University of Texas Medical Branch, Galveston, TX 77555, USA; [email protected] 3 Directorate of Environmental Health Effects Laboratory, Naval Medical Research Unit, Dayton, OH 45433, USA; [email protected] 4 Department of Comparative Medicine, University of Texas MD Anderson Cancer Center, Bastrop, TX 78602, USA; [email protected] 5 Institutional Office of Regulated Nonclinical Studies, University of Texas Medical Branch, Galveston, TX 77555, USA 6 NovoBiotic Pharmaceuticals, LLC, Cambridge, MA 02138, USA; [email protected] (D.E.H.); [email protected] (L.L.L.) * Correspondence: [email protected]; Tel.: +1-409-266-6919 Received: 21 August 2020; Accepted: 18 September 2020; Published: 22 September 2020 Abstract: The use of antibiotics is a vital means of treating infections caused by the bacteria Bacillus (B.) anthracis. Importantly, with the potential future use of multidrug-resistant strains of B. anthracis as bioweapons, new antibiotics are needed as alternative therapeutics. In this blinded study, we assessed the protective efficacy of teixobactin, a recently discovered antibiotic, against inhalation anthrax infection in the adult rabbit model. New Zealand White rabbits were infected with a lethal dose of B. anthracis Ames spores via the inhalation route, and blood samples were collected at various times to assess antigenemia, bacteremia, tissue bacterial load, and antibody production. Treatments were administered upon detection of B. anthracis protective antigen in the animals’ sera. For comparison, a fully protective dose of levofloxacin was used as a positive control. Rabbits treated with teixobactin showed 100% survival following infection, and the bacteremia was completely resolved by 24–48 h post-treatment. In addition, the bacterial/spore loads in tissues of the animals treated with teixobactin were either zero or dramatically less relative to that of the negative control animals. Moreover, microscopic evaluation of the tissues revealed decreased pathology following treatment with teixobactin. Overall, these results show that teixobactin was protective against inhalation anthrax infection in the rabbit model, and they indicate the potential of teixobactin as a therapeutic for the disease. Keywords: Bacillus anthracis; anthrax; inhalation; infection; antibiotic; rabbit model; protective antigen 1. Introduction Bacillus (B.) anthracis, the Gram-positive bacteria responsible for anthrax infection, has been a focus of the biodefense community for many years because of its past and potentially future use as a bioweapon [1,2]. Inhalation anthrax, which is one of four forms of the disease (the others are cutaneous, gastrointestinal, and injectional), is initiated upon inhalation of anthrax spores into the Pathogens 2020, 9, 773; doi:10.3390/pathogens9090773 www.mdpi.com/journal/pathogens Pathogens 2020, 9, 773 2 of 13 lungs [3]. While in alveolar spaces, the spores are phagocytosed by macrophages and dendritic cells that then migrate to regional lymph nodes. In the lymph nodes, the spores germinate, and the resultant bacteria multiply and eventually disseminate into the lymphatics, after which the bacteria enter the bloodstream (bacteremia). From circulation, the bacteria are capable of infecting various organs causing significant, widespread tissue pathology [3]. This ultimately leads to death of the host. In the germinated form, B. anthracis secrete a tripartite toxin, comprised of protective antigen (PA), lethal factor (LF), and edema factor (EF), which form the active toxins known as lethal toxin (LeTx) and edema toxin (EdTx) [4–6]. These toxins have been shown to bring about numerous pathological/pathophysiological effects due to their enzymatic abilities [6–8]. In recent years, there has been a renewed interest in this bacterial agent due to the growing concern for the development of multidrug-resistant (MDR) B. anthracis strains that could be used as bioweapons. While various antibiotics are currently effective against B. anthracis [3,9,10], some of which are included in the Strategic National Stockpile (SNS), these antibiotics could be rendered futile if the bacteria were genetically altered to become resistant [11]. Consequently, there is a continual need to discover and/or develop new therapeutics to combat this potential threat. Teixobactin is a recently discovered antibiotic produced by a species of β-proteobacteria named Eleftheria terrae, which belongs to a Aquabacteria-related genus [12,13]. This organism was discovered using the iChip, a multichannel device that can simultaneously isolate and grow uncultured bacteria [12,14,15]. Studies show that teixobactin, which is an unusual depsipeptide, has tremendous activity against Gram-positive bacteria, specifically by inhibiting cell wall synthesis. It accomplishes this by binding a highly conserved motif of lipid II and lipid III, which are precursors of peptidoglycan and cell wall teichoic acid, respectively [12,16,17]. Thus far, teixobactin has shown efficacy against Methicillin-resistant Staphylococcus aureus (MRSA), Methicillin-susceptible Staphylococcus aureus (MSSA), Vancomycin Intermediate Staphylococcus aureus (VISA), Vancomycin-resistant enterococci (VRE), Clostridium difficile, Streptococcus pneumoniae, Mycobacterium tuberculosis, and B. anthracis, either in vitro or in vivo. Astonishingly, the minimum inhibitory concentrations (MIC) for C. difficile and B. anthracis are as low as 5 and 20 ng/mL, respectively [12,18,19]. The targets of teixobactin are lipid II and lipid III. Lipid II, a peptidoglycan precursor, is composed of one bactoprenol hydrocarbon chain, a disaccharide of N-acetylglucosamine (GlcNAc) and N-acetylmuramic acid (MurNAc), a penta-peptide attached to the MurNAc, and a pyrophosphate group [20]. During bacterial cell wall synthesis, lipid II translocates across the cell membrane to deliver and incorporate its disaccharide and penta-peptide into the peptidoglycan network. In binding the pyrophosphate moiety and the first sugar moiety of lipid II, teixobactin inhibits the incorporation of the disaccharide-pentapeptide into the cell wall, which is a critical step in the cell wall synthesis pathway [16]. The other target of teixobactin is lipid III, a cell wall teichoic acid (WTA) precursor. WTAs are glycopolymers covalently attached to peptidoglycan via linkage to N-acetyl muramic acid sugars, and they account for as much as 60% of the cell wall mass in Gram-positive bacteria. WTAs play a variety of roles including cell shape determination, regulation of cell division, development of antibiotic resistance, and other fundamental facets of Gram-positive bacterial physiology [21–23]. When teixobactin binds lipid III, it blocks WTA biosynthesis which causes both the accumulation of toxic intermediates that are lethal to the bacteria as well as the liberation of autolysins that break down the peptidoglycan matrix [12]. As stated previously, the potential development and use of MDR B. anthracis strains for nefarious use is a matter of concern [24–27]. By introducing mutations into crucial bacterial proteins that are targets for current antibiotics, one could render the antibiotics ineffective. However, in the case of teixobactin, the targets are not proteins, but are highly conserved structural components of bacteria [12,16,17]. This suggests resistance through genetic modification of the targets would be very difficult to develop. In fact, resistance to teixobactin could not be obtained in strains of S. aureus and M. tuberculosis even when plating the bacteria on media with low concentrations of the antibiotic or Pathogens 2020, 9, 773 3 of 13 serial passaging in subinhibitory levels of the antibiotic [12]. Moreover, teixobactin was not toxic against mammalian NIH/3T3 and HepG2 cells at the highest concentration tested of 100 µg/mL [12]. In this blinded study, we evaluated the protection afforded by teixobactin against inhalation anthrax infection in the rabbit model. To our knowledge, this is the first reported work showing the therapeutic potential of teixobactin against inhalation anthrax in an animal model. 2. Results 2.1. Aerosol Infection Parameters The average infectious dose of B. anthracis Ames spores was 3.29 107 ( 5.60 106) colony × ± × forming units (cfu) which corresponds to 329 LD50 (50% lethal dose). The duration of aerosol infection, which varied among the animals since each animal was infected individually using real-time plethysmography, was approximately 19 minutes on average. Lastly, the average aerosol spray factor, which indicates aerosol efficiency of the spores, was 2.97 10 6. × − 2.2. Detection of Protective Antigen Blood samples were collected from each animal every 6 h beginning 12 h post-infection for detection of PA in serum. Upon detection of PA, the appropriate treatment was initiated for each animal. Among the treatment groups, PA was first detected as early as 12 h post-infection and as late as 36 h post-infection (Table1), but the majority of the animals were antigenemic by 18 to 24 h post-infection. The concentration of PA in the sera ranged from approximately 0.1 to 6.0 ng/mL with an average of 0.9 ng/mL. Table 1. Detection of protective antigen in rabbit sera. Animal Identification Time of PA Detection Concentration of PA Treatment Group Number (Time Post-Infection) (ng/mL) 4490 18 h 0.230 4493 24 h 1.000 4497 36 h 6.009 Teixobactin 4498 24 h 0.302 44873 18 h 0.566 44881 18 h 1.180 44882 24 h 0.170 4499 24 h 0.312 Levofloxacin 44874 18 h 0.419 4494 12 h 0.099 4496 30 h 0.360 Negative control 44872 24 h 0.817 44879 18 h 0.920 PA—protective antigen.
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