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(12) United States Patent (10) Patent No.: US 9,642,858 B2 Horzempa Et Al

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(12) United States Patent (10) Patent No.: US 9,642,858 B2 Horzempa Et Al USOO9642858B2 (12) United States Patent (10) Patent No.: US 9,642,858 B2 Horzempa et al. (45) Date of Patent: May 9, 2017 (54) USE OF RESAZURIN, OR ANALOGS (51) Int. Cl. THEREOF, FOR ANTIBACTERIAL A 6LX 3/535 (2006.01) THERAPY A6II 3/545 (2006.01) A6II 3/538 (2006.01) (71) Applicants: Joseph Andrew Horzempa, Pittsburgh, (52) U.S. Cl. PA (US); Dawn Marie Henson, CPC ........ A61K 3.1/5415 (2013.01); A61 K3I/538 Pittsburgh, PA (US); Gerard Joseph (2013.01) Nau, Sewickley, PA (US) (58) Field of Classification Search CPC .................................................... A61K 3.1A538 (72) Inventors: Joseph Andrew Horzempa, Pittsburgh, (Continued) PA (US); Dawn Marie Henson, Pittsburgh, PA (US); Gerard Joseph (56) References Cited Nau, Sewickley, PA (US) U.S. PATENT DOCUMENTS (73) Assignee: University of Pittsburgh-Of the 4.582,795 A * 4/1986 Shibuya ................... C12O 1/04 Commonwealth System of Higher 422,430 Education, Pittsburgh, PA (US) 4,719,094. A 1/1988 Rieckert et al. (Continued) (*) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 FOREIGN PATENT DOCUMENTS U.S.C. 154(b) by 0 days. EP 1242614 9, 2004 (21) Appl. No.: 14/439,651 EP 224.5176 8, 2012 (22) PCT Filed: Oct. 29, 2013 OTHER PUBLICATIONS (86). PCT No.: PCT/US2O13/O67296 International Search Report and Written Opinion from International PCT/US2013/067296, dated Jan. 29, 2014, 10pp. S 371 (c)(1), (2) Date: Apr. 29, 2015 (Continued) Primary Examiner — Shengjun Wang (87) PCT Pub. No.: WO2014/070760 (74) Attorney, Agent, or Firm — Klarquist Sparkman, PCT Pub. Date: May 8, 2014 LLP (57) ABSTRACT (65) Prior Publication Data A method for treating infection by bacteria in a Subject, US 2015/O258103 A1 Sep. 17, 2015 comprising administering to the Subject a therapeutically effective amount of resaZurin or a resaZurin analog, or a pharmaceutically acceptable salt or ester thereof, wherein Related U.S. Application Data the bacteria is selected from at least one of Francisella sp. (60) Provisional application No. 61/720.254, filed on Oct. or Neisseria sp. 30, 2012. 17 Claims, 15 Drawing Sheets Bacterial Strain choc choc 44M Res Francisellatularensis Schu S4 Etularensis WS Erovicida F. philonoragia Neisseria gonorrhoeae N. polysaccharea N. sicca Aciretobacter launcanni 122 A. aurani 19606 A. bauncanni 17978 Pseudomonas aeruginosa 1244 Escherichia Coli BL21 5almonella typhimurium T2 Staphylococcus aureus Listeria monocytogenes Klebsiellasp. Streptococcus pneumoniae US 9,642.858 B2 Page 2 (58) Field of Classification Search OTHER PUBLICATIONS USPC ....................................................... 514/229.8 Karuppusamy et al., “High Throughput Antibacterial Screening of See application file for complete search history. Plant Extracts by ResaZurin Redox with Special Reference to Medicinal Plants of Western Ghats.” Global Journal of Pharma cology, 3(2): 63-68, 2009. References Cited Drummond et al., “The development of microbiological methods (56) for phytochemical screening.” Recent Research Developments in Phytochemistry, 4: 143-152, 2000. (Abstract only). U.S. PATENT DOCUMENTS Sridharan, V. et al., “One-pot synthesis of symmetrically 4,834,042 A 5, 1989 Wakasa et al. disubstituted 3H-phenoxazin-3-ones by selective oxidative conden 4.954,630 A 9, 1990 Klein et al. sation with LTA.” Journal of Heterocyclic Chemistry, 44: 491-493, 5,304,645 A 4, 1994 Klein et al. 2007. 5,501.959 3, 1996 Lancaster et al. Wauven et al., “Pseudomonas aeruginosa mutants affected in 7,432,372 10, 2008 Batchelor et al. anaerobic growth on arginiae: evidence for a four-gene cluster 8,017,606 9, 2011 Andries et al. encoding the arginine deiminase pathway,” Journal of Bacteriology, 2003, OO869 16 5/2003 Goligorsky ............ A61K 31.00 160(3): 928-934, 1984. 424.944 Schmitt et al., “Antibacterial activity of resaZurin-based compounds 2011 OO15137 1, 2011 Cottarel ............. A61K 31/4745 against Neisseria gonorrhoeae in vitro and in vivo.” International 514, 21.1 Journal of Antimicrobial Agents, Jul. 19, 2016. 2011 OO86341 A1 4/2011 Batchelor et al. 2011/O177605 A1 T 2011 Unkrig et al. * cited by examiner U.S. Patent May 9, 2017 Sheet 1 of 15 US 9,642,858 B2 U.S. Patent May 9, 2017 Sheet 2 of 15 US 9,642,858 B2 5 er w w w w sYYYYYYYYYYYY SwYYYYYYYYYYY s swYYYYYYYYYYY SwYYYYYYYYYYY R SwYYYYYYYYYYY SwYYYYYYYYYYY SwYYYYYYYYYYY sSY re- C C CO a to L S (r. 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U.S. Patent May 9, 2017 Sheet 12 of 15 US 9,642,858 B2 FIG. 12 U.S. Patent US 9,642,858 B2 it info" U.S. Patent May 9, 2017 Sheet 14 of 15 US 9,642,858 B2 te se (twfisy) (rai is fees it (S8& US 9,642,858 B2 1. 2 USE OF RESAZURIN, OR ANALOGS Another embodiment disclosed herein relates to a method THEREOF, FOR ANTIBACTERIAL for inhibiting bacteria growth, comprising contacting an THERAPY effective amount of resaZurin or a resaZurin analog, or a pharmaceutically acceptable salt or ester thereof, with at CROSS REFERENCE TO RELATED least one of Francisella sp. or Neisseria sp. APPLICATIONS A further embodiment disclosed herein relates to a method for inhibiting the growth of at least one of Franci This is the U.S. National Stage of International Applica sella sp. or Neisseria sp. on a Substrate, comprising con tion No. PCT/US2013/067296, filed Oct. 29, 2013, which tacting the Substrate with resaZurin or a resaZurin analog, or was published in English under PCT Article 21(2), which in 10 a pharmaceutically acceptable salt or ester thereof. turn claims the benefit of the earlier filing date of U.S. Also disclosed herein is an antibacterial composition Provisional Application No. 61/720.254, filed Oct. 30, 2012. comprising resaZurin or a resaZurin analog, or a pharmaceu The entire disclosure of the prior applications are considered to be part of the disclosure of the accompanying application tically acceptable salt or ester thereof, and at least one 15 pharmaceutically acceptable additive. and are incorporated herein by reference. The foregoing will become more apparent from the fol BACKGROUND lowing detailed description, which proceeds with reference to the accompanying figures. Neisseria is a genus of Gram (-) bacteria included among the proteobacteria, a large group of Gram-negative bacteria. BRIEF DESCRIPTION OF THE DRAWINGS Neisseria are diplococci and the genus includes the species N. gonorrhoeae (also called the gonococcus), which causes FIG. 1 is a graph showing the results of testing resaZurin gonorrhea, and N. meningitidis (also called the meningo against several bacteria species. coccus), one of the most common causes of bacterial men FIG. 2 is a graph indicating that F. tularensis growth is ingitis and the causative agent of meningococcal septicae 25 inhibited by resaZurin. mia. There are over 100 million new cases of gonorrhea FIG. 3 is a graph indicating that resaZurin is bactericidal annually, making N. gomorrhoeae the second most common to F tularensis. sexually transmitted infectious bacterium. A closely related FIG. 4 is a graph indicating that resaZurin reduces bac organism, N. meningitidis can cause a number of diseases, terial burden during infection of HEK-293 cells. Such as meningitis, fulminant septicemia, and bacteremia. 30 FIG. 5 is a graph indicating that resaZurin reduces bac Antimicrobial resistance and decreasing Susceptibility of terial burden during infection of primary human macro Neisseria species to extended-spectrum drugs has under phages. scored the need for the development of new antibiotics that FIG. 6 is a graph indicating that resaZurin and resorufin target pathogenic organisms in this genus. are bactericidal to F tularensis. Francisella is a genus of Gram (-) bacteria that are 35 FIG. 7 is a graph indicating that resaZurin does not have coccobacillary or rod-shaped, non-motile organisms, which an antimicrobial effect on Escherichia coli. are also facultative intracellular parasites of macrophages. F. FIG. 8 is a graph indicating that resaZurin does not have tularensis causes tularemia (also known as rabbit fever). F. an antimicrobial effect on Pseudomonas aeruginosa. novicida and F. philomiragia are associated with septicemia FIG. 9 is a graph indicating that the minimal inhibitory and invasive systemic infections. The preferred course of 40 concentration of resaZurin against F. tularensis is 4.4 uM. treatment for tularemia is antibiotic therapy. F tularensis is FIG. 10 is a graph indicating that resorufin exhibits a naturally resistant to B-lactam antibiotics such as penicillin.
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