Technical Background.  Laboratory studies conducted by Oragenics’ scientists and outside contract research firms have demonstrated MU1140’s effectiveness against essentially all tested Gram-positive bacteria and certain medically important Gram-negative bacteria as well.  Bacteria, including those responsible for “strep throat”, common pneumonia, gastric ulcers, and listeriosis, are killed by MU1140.  This antibiotic molecule belongs to a new class of antibiotics called lantibiotics.  Lantibiotics differ from other antibiotics because they contain an unusual amino acid.  They are able to kill a wide variety of bacteria by binding to a cell wall component, Lipid II, a molecule that is essential for bacterial cell growth.

Preclinical Studies.  By mid-2005, Oragenics’ scientists had made significant breakthroughs in the production and purification of MU1140 using optimized fermentation processes and initiated preclinical studies.  Two laboratory studies with MU1140, utilizing independent testing labs, provided positive results on Tier 2 spectrum of activity against clinically important Gram-positive bacteria, including Staph aureus, Enterococcus faecalis, and Clostridium difficile.  It has been further demonstrated that MU1140 has a novel mechanism of kill and that the lantibiotic is effective in two infectious animal models against Staph. aureus infection.  A particularly interesting feature of MU1140 is that none of the sensitive species of bacteria tested were able to acquire genetically stable resistance to purified MU1140.  Acquired resistance to antimicrobial agents by strains of bacteria that cause illness in humans has become a significant issue for infectious disease control today.
The major hurdle to further evaluation of this antibiotic candidate in humans has been the inability to manufacture sufficient material that is of sufficient purity to meet FDA standards for human use.  This is the same reason that none of the other 50+ lantibiotics reported in the literature has been tested as a new drug.  Oragenics scientists have overcome this hurdle by devising a synthetic chemistry approach (the Company’s DPOLT™ technology) to producing analogs of MU1140.  This program was supported, in part, by competitive Small Business Innovative Research (SBIR) Phase 1 and II grants from the National Science Foundation.  In December 2008, the Company reported that its scientists had successfully employed its proprietary synthetic chemistry platform to produce an active analog of MU1140.  Oragenics also announced at that time that the Company had retained Almac Sciences of the UK, a leading contact manufacturing firm, to refine and scale-up GMP production of the synthetic MU1140 analog for it to be fully tested for regulatory approval as a new antibiotic drug.

Regulatory Status.  Oragenics expects to receive sufficient GMP quality MU1140 material in 2009 from its contract manufacturer, Almac Sciences, to complete additional preclinical animal safety studies, and then to prepare and file an Investigational New Drug (IND) application with the FDA to begin Phase 1 human safety trials with MU1140 in early 2010.

General Interest Articles (Click links below to view articles)
Parade Magazine – A Deadly Bug Invades Our Towns
December 7, 2008 article discusses the threat of methicillin-resistant Staphylococcus aureus (MRSA) infections outside hospital walls.

New England Journal of Medicine – Antibiotic-Resistant Bugs in the 21st Century – A Clinical Super-Challenge
January 29, 2009 describes the problem of eradicating infections caused by antibiotic-resistant “superbugs” and the situation of a dry pipeline for new antimicrobials.

Antimicrobial Resistance Response to a Growing Problem
This statement from the National Institutes of Health discusses the emerging problem of antibiotic resistance.

Mutacin 1140: Scientific Articles (Click links below to view articles if available)

Smith, L., Hasper, H., Breukink, E., Novak. J., Cerkasov, J., Hillman, J.D., Wilson-Stanford, S. and Orugunty, R.S. 2008. Elucidation of the antimicrobial mechanism of Mutacin 1140. Biochemistry 47: 3308-3314.

Smith, L. and Hillman, J.D. 2008. Therapeutic potential of type A (I) lantibiotics, a group of cationic peptide antibiotics. Current Opin in Micro 11: 401-408.

Hasper, H.E., Kramer, N.E., Smith, J.L., Hillman, J.D., Zachariah, C., Kuipers, O.P., de Kruijff, B. and Breukink, E. 2006. An alternative bactericidal mechanism of action for lantibiotic peptides that target Lipid II. Science 313: 1636-1637.

Smith, J.L., Orugunty, R. and Hillman, J.D. Lantibiotic production by Streptococcus mutans: their uses in replacement therapy for the prevention of dental caries and as antibiotics for the treatment of various infectious diseases. Horizon Scientific Press, Rowan House, 28 Queens Road, Hethersett, Norwich, NR9 3DB, UK, in press.

Smith, L., Zachariah, C., Thirumoorthy, R., Rocca, J., Novak, J., Hillman, J.D. and Edison, A.S. 2003. Structure and dynamics of the lantibiotic Mutacin 1140. Biochem 42: 10372-10384.

Smith, L., Novak, J., Rocco, J., McClung, S., Hillman, J.D. and Edison, A.S. 2000. Covalent structure of Mutacin 1140 and a novel method for the rapid identification of lantibiotics. Eur J Biochem 267: 6810-6816.

Hillman, J.D., Novak, J., Sagura, E., Gutierrez, J.A., Brooks, T.A., Crowley, P.J., Hess, M., Azizi, A., Leung, K.P., Cvitkovitch, D. and Bleiwesis, A.S. 1998. Genetic and biochemical analysis of Mutacin 1140, a lantibiotic from Streptococcus mutans. Infection and Immunity 66: 2743-2749.

Hillman, J.D., Yaphe, B.I. and Johnson, K.P. 1985. Colonization of the human oral cavity by a strain of Streptococcus mutans. J Dent Res 64: 1272-1274.

Hillman, J.D., Johnson, K.P. and Yaphe, B.I. 1984. Isolation of a Streptococcus mutans strain producing a novel bacteriocin. Infection and Immunity 44: 141-144.