Bacterial pathogens are becoming increasingly resistant to multiple antibiotics, rendering what were once considered miracle cures ineffective (Cohen M L. 2000. Nature. 406:762-767). Without these medicines, clinicians must resort to alternative drugs. Often these drugs are less effective than their predecessors, and they have more side effects. Worse, in some instances, alternative drugs are not an option. Pathogens have been isolated that are resistant to all of the Federal Drug Administration's (FDA) approved antibiotics (Mahgoub S, et al. 2002. Infect Control Hosp Epidemiol. 23:477-479). These organisms are intractable pathogens, the harbingers of civilization's return to a pre-antibiotic era and the suffering this era would entail.
Both in its depth and breath, the problem of antibiotic resistance in pathogens is growing. These pathogens quickly arise and spread. To a large degree, this phenomenon is the result of the rapid acquisition and dissemination of genes that confer antibiotic resistance (D'Costa V M, et al. 2006. Science. 311:374-377; Walsh C 2003. Antibiotics: Actions, Origins, Resistance, ASM Press, Washington, D.C.). Bacteria, even of different genera, can share resistance elements through the processes of transformation, transduction, and conjugation (Mazel D & Davies J. 1999. Cell Mol Life Sci. 56:742-754). As a direct consequence of this transfer, antibiotic resistance genes in the environment have become ubiquitous, and pan-antibiotic-resistant pathogens have emerged. Without swift and creative action by the research and development community, infection may once again become the leading cause of suffering and death in the world.
Present day examples of superbugs are MRSA (methicillin resistant Staphylococcus aureus) (McDougal, et al., 2003. J. of Clin. Microb., November, p. 5113-5120 Vol. 41, No. 11) and MDR (multi-drug resistant) Acinetobacter baumannii. Collectively, these organisms are responsible for over forty-percent of all nosocomial infections and over fifty-percent of dermatological infections that require hospitalization (Bassetti M, et al. 2009. Fut. Microbiol. 3:649-660; Frazee B W, et al. 2005. Ann Emerg Med. 45:311-320). All the current oral treatment options for MRSA have drawbacks (Chambers H F & Hegde S S. 2007. Expert Rev Anti Infect Ther. 5:333-335). Linezolid is very expensive, counter indicated for long term therapy, and has notable toxicities including myelotoxicity, lactic acidosis, serotonin syndrome, and peripheral neuropathy (Garazzino S, et al. 2007. Int J Antimicrob Agents. 29:480-483; Garrabou G, et al. 2007. Antimicrob Agents Chemother. 51:962-967; Lawrence K R, et al. 2006. Clin Infect Dis. 42:1578-1583). MRSA are becoming increasingly resistant to tetracyclines, fluoroquinolones, clindamycin, and vancomycin, and these antibiotics are rapidly becoming non-effective treatments (Kaka A S, et al. 2006. J Antimicrob Chemother. 58:680-683). Furthermore, sulfamethoxazole-trimethoprim has recently been shown to have a treatment failure rate of fifty-percent (Proctor R A. 2008. Clin Infect Dis. 46:584-593).
The situation for MDR A. baumannii is also troubling. MDR strains of this organism have been isolated that are resistant to all approved frontline and secondary antibiotics (Maragakis L L & Perl T M. 2008. Clin Infect Dis. 46:1254-1263). Without effective treatments, patients with MRSA or MDR A. baumannii infections have longer periods of hospitalization, increased morbidity, and a greater likelihood of in-hospital death (Bassetti M, et al. 2009. Fut Microbiol. 3:649-660; Frazee B W, et al. 2005. Ann Emerg Med. 45:311-320).
Antibiotic resistance problem is not limited in its scope to medical settings. Antibiotic uses and misuses in veterinary science and in agriculture are a global and rapidly growing issue. For example, “fire blight, caused by Erwinia amylovora, is a major threat to apple and pear production worldwide. Nearly all pear varieties and many of the most profitable apple varieties and horticulturally-desirable rootstocks planted throughout the U.S. are highly susceptible to fire blight. Therefore, most growers apply the antibiotics streptomycin or oxytetracycline one to three times during bloom to prevent growth of E. amylovora. Although streptomycin and oxytetracycline are effective in preventing fire blight on blossoms, their application likely drives antibiotic resistance in the environment and in the food chain. Innovative approaches are desperately needed to reign in fire blight, a disease that has been smoldering in orchards for more than a century and raging out of control over the past decade. An additional societal benefit of non-conventional treatments of fire blight is the elimination of the bulk of antibiotic use in plant agriculture, since greater than 90% of antibiotics applied to plants is for the control of that disease (Johnson, K. B., and Stockwell, V. O. 2000. Biological control of fire blight. Pages 319-337 in: Fire Blight—the Disease and its Causative Agent, Erwinia amylovora, J. L. Vanneste, ed. CAB International, New York).
What is needed are new treatments for microbial infections in animals, plants and environmental settings.
USPTO Backgrounds
USPTO Backgrounds