What The World Needs Now: Safe Non-Antibiotic Anti-Infectives

Main Category: MRSA / Drug Resistance
Also Included In: Infectious Diseases / Bacteria / Viruses;  Biology / Biochemistry
Article Date: 29 Oct 2008 - 5:00 PDT

email to a friend   printer friendly   opinions  

With today's first line antibiotics slowly losing their ground against nature's hard- to- kill pathogens, pharmaceutical researchers are looking for new classes of compounds and targets that have low potential for the development of resistance.

At the upcoming first-ever joint meeting of the American Society for Microbiology and the Infectious Diseases Society of America (48th Annual ICAAC/IDSA 46th Annual Meeting, October 25-28, 2008, in Washington, D.C.), Emeryville, CA.-based NovaBay Pharmaceuticals presented four posters and an oral presentation regarding the company's topical anti-microbial program.

"The posters presented at ICAAC 2008 provide, for the first time, a comprehensive description of the chemical properties and biological activity of our lead compound NVC-422," said Dr. Bez Khosrovi, VP of Research and Development. "NVC-422, as a topical non-antibiotic antimicrobial, offers the opportunity for the treatment and prevention of a wide range of non-systemic infections without the development of resistance thus preserving antibiotics for the treatment of systemic infections."

The first poster describes the chemistry and basic biology of NovaBay's clinical compound, NVC-422, a broad-spectrum, non-antibiotic antimicrobial belonging to N-chloroamine class of naturally occurring antimicrobials. Neutrophils, disease-fighting white blood cells, produce the related and less stable compound N-chlorotaurine and N,N-dichlorotaurine, from taurine and hypochlorous acid, to destroy invading pathogens. These endogenous molecules are part of an innate anti-bacterial defense mechanism but unfortunately are not stable enough to be used as therapeutic agents. NVC-422, named as N,N-dichloro-2,2-dimethyltaurine, is synthesized by treating 2,2-dimethyltaurine with chlorinating agents.

By substituting hydrogens on ß carbon with methyl groups in taurine, NovaBay scientists created a stable molecule that is potent and fast-acting against pathogens such as S. aureus and E. coli. NVC-422 is currently in preclinical and early clinical testing for preventing or treating a number of infections and conditions. These include eradication of potentially deadly methicillin-resistant Staphylocccus aureus (MRSA) from hospital patients, and the prevention of infections from urinary tract catheters (the most common source of hospital infections) and from central venous catheters. It is also in development for the treatment of skin infections.

A second poster describes the detailed biological activity and time-kill studies of NVC-422 against a wide range of standard laboratory microbial strains as well as recent clinical isolates from ophthalmic, wound, and urinary sources. Gram-positive bacteria, Gram-negative bacteria, antibiotic resistant bacteria, MRSA strains producing the Panton-Valentine leukocidin (PVL) toxin as well as eukaryotic yeasts were all susceptible to NVC-422. The minimum bactericidal concentrations (MBCs) ranged from 0.12 to 4 micrograms per milliliter (µg/mL) for bacteria and 16 to 32 µg/mL for yeasts, levels that are well below concentrations of NVC-422 used clinically. NVC-422 showed rapid killing (> 3 log reduction) against a wide range of organisms even at concentrations close to their MBC values. The compound was also active against bacteria encased in protective biofilm. Finally, the in vitro therapeutic index (ratio of MBC to cytotoxicity) of NVC-422 is substantially higher than those of commonly used biocides.

The third poster examines more closely the use of NVC-422 against organisms in biofilms - troublesome protective "communities" of microorganisms that adhere to living or inert surfaces (e.g. catheters or medical implants). Approximately 800,000 patients in U.S. hospitals and outpatient settings develop urinary tract infections as a result of biofilms forming within their urinary catheters. Individuals who are permanently catheterized (e.g. paraplegics), must take antibiotics for their entire lives to prevent biofilm-induced infections even though the treatment is generally ineffective in eliminating the biofilm. Patients on life-long antibiotic regimens experience frequent, sometimes life-threatening side effects. This poster describes the development of a biofilm model and the efficacy of NVC-422 against bacteria in catheter biofilms.

Treatment of urinary tract pathogens P. aeruginosa, S. aureus, P. mirabilis, and C. albicans (planktonic or in biofilm) with NVC-422 resulted in 99.9% reduction in colony-forming units for these pathogens. At the same time, NVC-422 had relatively little cytotoxicity to cultured human bladder cells resulting in an in vitro therapeutic index of greater than 1,000 (i.e. the toxic dose is 1,000 times the effective dose) for the bacterial strains tested

In the final poster, NovaBay scientists address the possibility of the development of spontaneous resistance to NVC-422. Their study suggests that NVC-422 is highly unlikely to give rise to such resistance. NovaBay investigators tested NVC-422 against E. coli, P. aeruginosa, and S. aureus. Surviving bacteria were considered resistant if their MBC was raised by a factor of four or more but scientists found no resistant isolates of the bacteria tested (frequency of resistance <2 x 10-10), demonstrating that these pathogens possess a very low likelihood of developing resistance to NVC-422. Moreover, bacteria that are resistant to antibiotics in current clinical use are not cross-resistant to NVC-422.

"We are proud of the progress we have made in our research and clinical development of antimicrobial compounds and are delighted to have been invited to present an oral summary at this prestigious conference," said Dr. Ron Najafi, CEO of Novabay Pharmaceuticals. "We would like to acknowledge the contributions of the scientists who generated the data summarized in these posters. We will continue to endeavor to find additional applications for these antimicrobial compounds against a number of indications to improve people's health and ultimately save lives."

For more information, log on to www.novabaypharma.com

• Additional
• References
• Citations