Synereca Pharmaceuticals is developing a novel therapeutic that enhances the utility of existing classes of antibiotics for use as a combination antibacterial against multidrug-resistant (MDR) bacterial pathogens, with an initial focus on MDR Gram-negative respiratory infections.
In the US alone, an estimated 2 million people acquire antibiotic-resistant infections annually, resulting in at least 23,000 deaths and adding over $20 billion in direct healthcare costs (1). The European Medicines Agency estimated Europe’s figure at over 2.5 million resistant infections and 25,000 deaths annually (2). In the UK government-commissioned “Review on Antimicrobial Resistance” report, deaths attributable to antimicrobial resistance worldwide reached 700,000 in 2014, and are expected to rise to more than 10 million by 2050, making antimicrobial resistant infections a leading cause of death over the coming decades (3). Unfortunately, since 1962, only 3 new classes of antimicrobial agents have been introduced; consequently, antimicrobial resistance (AMR) is now an international health crisis, deemed by the World Health Organization as a “grave global problem” and a major threat to public health worldwide (4). Thus, new drugs and new approaches to this global issue are greatly needed.
The Infectious Disease Society of America has brought particular emphasis to a specific faction of antibiotic-resistant bacteria termed ESKAPE pathogens; these are the most common MDR and extensively drug-resistant bacteria and represent the most serious health threats. The ESKAPE group includes Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp (5). Bacterial infections involving the Gram-negative ESKAPE pathogens (K. pneumoniae, A. baumannii, P. aeruginosa, and Enterobacter), are of particular concern as there are few antibacterial agents with activity against MDR Gram-negative pathogens. Indeed, in a report by the CDC showed that a startling 63% of A. baumannii isolates and 19% of P. aeruginosa isolates were resistant to multiple antibiotics. Carbapenem-resistant Enterobacteriaceae (which includes K. pneumoniae and E. coli) cause more than 9,000 infections in the United States each year, and about 600 of these infections are fatal (1). Because of the resistance profiles of emerging strains, the overuse of existing antibiotics, and the lack of Gram-negative therapeutics, there is great need for new Gram-negative therapies.
Synereca’s scientific founder, Professor Scott Singleton, and his colleagues screened over 130,000 compounds and identified five separate chemical classes of antibiotic potentiators. Since that screen, Synereca’s SAR campaign has resulted in the synthesis of over 700 novel compounds in 7 structural classes that potentiate the activity of colistin. Colistin is currently used as a drug of last resort against serious Gram-negative bacterial infections. The use of colistin has increased as the incidence of multi-drug resistant Gram-negative bacteria has grown, despite its adverse effect profile. Unfortunately, as colistin use increases, resistant strains are now emerging. Synereca’s small molecules have the potential to broaden the use of colistin for serious in-patient bacterial infections, reduce the doses required to induce bacterial killing, and improve the treatment of multi-drug-resistant pathogens.
Synereca has identified colistin potentiators that have demonstrated enhancements of up to 4,000-fold in the potency of colistin against colistin-resistant strains A. baumannii, K. pneumoniae, and P. aeruginosa. Early candidate compounds showed a 4-fold reduction in the protective dose of colistin in a murine bacteremia model using an extensively multi-drug resistant strain of Acinetobacter baumannii (Ab23; MIC >32 µg/ml for colistin, meropenem, ciprofloxacin, tobramycin, and levofloxacin). In a murine K. pneumoniae respiratory infection model with a colistin-resistant K. pneumoniae isolate (colistin MIC = 64 µg/ml), the combination of colistin plus potentiator demonstrated a 1-log drop in the bacterial lung burden at 12 hours compared to colistin alone. Lead candidate compounds are currently being assessed for in vivo safety, pharmacokinetics, and efficacy to determine a final IND candidate.
Colistin potentiation has clinical application in several contexts. Initially, Synereca is developing an inhaled product for use in combination with colistin. Inhaled colistin is an approved treatment in the EU and is frequently used off-label in the US. We believe that the most viable use for an inhaled combination product is hospital-acquired and potentially ventilator-associated pneumonia (HAP/VAP) suspected or proven to be caused by MDR Gram-negative bacteria. Cystic fibrosis patients experiencing chronic infections and patients with bronchiectasis could also benefit from Synereca’s product.
- Antibiotic Resistance Threats in the United States Report, 2013 http://www.cdc.gov/drugresistance/threat-report-2013/
- The bacterial challenge: time to react. A call to narrow the gap between multidrug-resistant bacteria in the EU and the development of new antibacterial agents. EMEA. 2009 http://ecdc.europa.eu/en/publications/Publications/0909_TER_The_Bacterial_Challenge_Time_to_React.pdf
- Review on Antimicrobial Resistance. Antimicrobial Resistance: Tackling a Crisis for the Health and Wealth of Nations. 2014. http://amr-review.org/sites/default/files/AMR%20Review%20Paper%20-%20Tackling%20a%20crisis%20for%20the%20health%20and%20wealth%20of%20nations_1.pdf
- Ventola CL. The Antibiotic Resistance Crisis: Part 1: Causes and Threats. Pharmacy and Therapeutics. 2015;40(4):277-283.
- Boucher HW, Talbot GH, Bradley JS, Edwards JE, Gilbert D, Rice LB, et al. Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America. Clin Infect Dis. 2009; 48: 1-12.