Our Programs

Multidrug-resistant bacterial infections

According to the World Health Organization (WHO), multidrug-resistant (MDR) bacterial pathogens, commonly known as “superbugs”, are among the most serious threats to public health.1,2

Bacteria are developing resistance to all known antibiotics,3,4 and the rate of resistance development is occurring at a faster pace than pharmaceutical companies are able to introduce new drugs to market. Even when novel antibiotics are discovered, resistant strains of bacteria rapidly evolve,5 and it is becoming more and more difficult for drug makers to develop products that will effectively treat MDR bacterial infections.6

Antibiotic-resistant bacteria cause more than two million infections per year in the US, resulting in ~20,000 deaths. These infections result in an estimated $20 billion in direct healthcare costs and $35 billion in lost productivity7 and these costs are expected to rise rapidly over the next several years.8 The threat of antibiotic resistance is especially critical in the case of Gram-negative bacterial pathogens, such as Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae.

Infections caused by MDR Gram-negative bacteria result in a higher mortality rate, longer hospital stays and larger treatment costs compared to antibiotic-susceptible infections. Patients with MDR Gram-negative bacterial infections have a mortality rate of 30-70%,9 which is approximately two to three-fold higher than patients who have an antibiotic-susceptible infection.10

Clearly, a new effective treatment for MDR Gram-negative bacterial infections would provide an immediate, desperately needed solution to one of the most dire problems impacting global health.


Agile Sciences’ 2-AI molecules have the potential to overcome bacterial resistance elements so as to restore the efficacy of multiple antibiotics that are currently inactive against MDR Gram-negative bacterial strains. The 2-AI molecules are widely active across multiple bacterial species, and are able to effectively overcome multiple antibiotic resistance mechanisms. Therefore, these molecules have the potential to provide clinicians with a substantially improved method for treating MDR Gram-negative bacterial infections.

Agile Sciences is currently evaluating the spectrum of activity of a lead compound for this application. The lead compound, AGL-503, was able to restore the activity of meropenen against a carbapenem-resistant strain of Pseudomonas aeruginosa in an acute murine lung infection model. Additionally, a medicinal chemistry program is underway to identify additional compounds.

Lung infections in cystic fibrosis patients

Pulmonary infections are the leading cause of mortality in cystic fibrosis (CF) patients.11,12 Pseudomonas aeruginosa is the most commonly isolated organism from these infections,13 and the prevalence of multidrug-resistant (MDR) strains of this bacterium is increasing rapidly, with 20% of CF patients testing positive for MDR P. aeruginosa in 2009.14

Existing antibiotic therapies are unable to eradicate lung infections in CF patients, and current antibiotics are particularly ineffective against MDR strains of P. aeruginosa. Therefore, an urgent need exists for a therapeutic that will more effectively treat lung infections of CF patients.

Lung infections in CF patients are particularly recalcitrant to current therapeutic options due to the ability of bacteria to resist antibiotic treatment through biofilm formation and other drug resistance mechanisms.15,16


Agile Sciences’ technology presents a novel solution to circumventing these bacterial defense mechanisms. Our proprietary 2-aminoimidazole (2-AI) small molecules, derived from a metabolite of a sea sponge, overcome antibiotic resistance by dispersing bacterial biofilms and lowering the minimum inhibitory concentration (MIC) values of antibiotics toward bacteria.17,18,19,20 When used in combination with current antibiotic therapies, such as tobramycin, the 2-AI compound has the potential to allow the antibiotic to work more effectively by eliminating biofilms and antibiotic resistance.

Agile Sciences is currently evaluating a lead compound, AGL-503, as a combination treatment along with tobramycin for this application. The program is currently evaluating aerosol delivery of the compound in a mouse model of cystic fibrosis. The project is funded by a Phase II STTR grant from the NIH.

Chronic wound infections

Chronic wounds are defined as those that fail to heal through an orderly and timely reparative process.21 Approximately 6.5 million patients are afflicted with chronic wounds in the U.S. each year, and the burden is growing rapidly due to the increasing aging population and the rise in the incidence of diabetes.22 Chronic wounds result in severe psychological, social, and economic burdens, and the estimated financial cost associated with treating chronic wounds in the U.S is estimated to be $10-$25 billion per year.22,23

Wound pathogenesis is dependent on multiple factors, including the bacterial species that are present as well as bacterial load.22,24 As with other persistent infections, bacterial colonization in the form of biofilms has been shown to delay healing.25,26,27 Biofilms provide a protective environment for bacteria, increasing their resistance to antimicrobials and to the host immune response. Once established, biofilms are extremely difficult to eradicate, and studies have shown that many topical agents and wound dressings are ineffective against biofilm infections.


Agile Sciences has developed a novel approach for eradicating biofilms present in chronic wounds. The Company’s 2-AI small molecules exhibit broad bacterial biofilm inhibition and dispersal properties against both Gram-positive and Gram-negative bacteria. The 2-AI molecules act to dismantle the biofilm community into single, free-floating bacteria allowing antimicrobials to work on the planktonic form of the bacteria toward which they are most effective.28,29,30 The 2-AI molecules have been shown to inhibit and disperse bacterial biofilms of strains relevant to chronic wounds, are active under flow conditions, and are non-microbicidal.

Agile Sciences is evaluating the effectiveness of a lead 2-AI compound, AGL-110, in combination with silver for use as a topical treatment for chronic wound infections. AGL-110 has been shown to have anti-biofilm activities against Staphylococcus aureus and Pseudomonas aeruginosa, two bacteria that are often responsible for chronic wound infections. Additionally, AGL-110 has been classified as a non-irritant using an in vitro human tissue mimic. Currently, the in vivo efficacy of AGL-110 in combination with silver is investigated using a rabbit ear wound model and a pig wound model.

Sources

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  2. Anzaldi, L.L. and E.P. Skaar, The evolution of a superbug: how Staphylococcus aureus overcomes its unique susceptibility to polyamines. Mol Microbiol, 2011. 82(1): p. 1-3.
  3. Arias, C.A. and B.E. Murray, Antibiotic-Resistant Bugs in the 21st Century — A Clinical Super-Challenge. New England Journal of Medicine, 2009. 360(5): p. 439-443.
  4. Bush, K., et al., Tackling antibiotic resistance. Nature Reviews Microbiology, 2011. 9(12): p. 894-896.
  5. Mangili, A., et al., Daptomycin-resistant, methicillin-resistant Staphylococcus aureus bacteremia. Clin Infect Dis, 2005. 40(7): p. 1058-60.
  6. Lehr, P., Healthcare-Acquired Infection: Devices, Pharmaceuticals, and Environmental Products, B. Research, Editor 2011.
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  8. Economic Aspects of Antibiotic Resistance, in ReAct facts2008.
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  10. Carmeli, Y., et al., Health and economic outcomes of antibiotic resistance in Pseudomonas aeruginosa. Arch Intern Med, 1999. 159(10): p. 1127-32.
  11. Govan, J.R. and V. Deretic, Microbial pathogenesis in cystic fibrosis: mucoid Pseudomonas aeruginosa and Burkholderia cepacia. Microbiol Rev, 1996. 60(3): p. 539-74.
  12. Parkins, M.D., J.C. Rendall, and J.S. Elborn, Incidence and risk factors for pulmonary exacerbation treatment failures in patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa. Chest, 2012. 141(2): p. 485-93.
  13. Gibson, R.L., J.L. Burns, and B.W. Ramsey, Pathophysiology and management of pulmonary infections in cystic fibrosis. Am J Respir Crit Care Med, 2003. 168(8): p. 918-51.
  14. Cystic Fibrosis Foundation Patient Registry Annual Data Report to the Center Directors 2009. 2010.
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  20. Melander, C., Cavanagh, J., Huigens, R., Ballard, T., Richards, J., Inhibition of bacterial biofilms with imidazole derivatives, 2011, North Carolina State University: United States.
  21. Lazarus, G.S., et al., Definitions and guidelines for assessment of wounds and evaluation of healing. Arch Dermatol, 1994. 130(4): p. 489-93.
  22. Sen, C.K., et al., Human skin wounds: a major and snowballing threat to public health and the economy. Wound Repair Regen, 2009. 17(6): p. 763-71.
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  29. Lindsey, E.A., et al., 2-Aminopyrimidine as a novel scaffold for biofilm modulation. Org Biomol Chem, 2012. 10(13): p. 2552-61.
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