Orally available tRNA Synthase Inhibitors as a differentiated treatment for methicillin-resistant staphylococcus aureus infection

Unmet Need

Gram(+) bacteria such as Staphylococcus, Streptococcus, and Enterococcus are major human pathogens responsible for a large number of life-threatening infections. Antibiotic resistant strains such as methicillin resistant Staphylococcus aureus (MRSA) and vancomycin resistant Enterococcus (VRE) are widespread and limit the effectiveness of available antibiotics.  CDC statistics show that there are 80,461 severe infections and 11,285 deaths due to MRSA per year in the USA. Similarly, there are 20,000 infections and 1300 deaths per year due to VRE.

A new class of antibiotic will provide an important alternative for patients with class-specific drug allergies or with contraindications such as drug-drug interactions. The focused Gram(+) activity of our novel compounds will lead to less resistance in Gram(-) gut flora and potentially less risk for antibiotic associated diarrhea or C. difficile superinfections. Finally, many antibiotics in use for Gram(+) infections are glycopeptides or lipopeptides that can only be administered by parenteral routes due to their low oral bioavailability. Antibiotics with an option for IV administration and oral step down regimen are urgently needed for acute bacterial skin and skin structure infections (ABSSSI), where parenteral treatment may only be necessary for the first few days of treatment or often not at all.

Solution & Benefits

In the past 5 years, the University of Washington (UW) group has synthesized and tested over 500 new methionyl-tRNA synthetase (MetRS) inhibitors in an NIH-funded project to develop therapeutics for human African trypanosomiasis. This disease requires both oral bioavailability and CNS penetration of the drug. Significant progress was made in achieving oral bioavailability in several series of compounds, which opened an avenue to explore application of these MetRS inhibitors for other therapeutic applications. With funding from the UW, our collaborators recently started investigations into the antibiotic activity of these inhibitors and immediately identified compounds with low MICs against MRSA and other Gram(+) bacteria, with the following therapeutic benefits:

• Novel biochemical target, the bacterial MetRS enzyme. No antibiotics have yet been approved that act on this target.

• Improved oral bioavailability, from <10% to ~80%, while retaining or even improving potency against the biochemical target.

• Patented composition of matter claims, PCT/US2015/046357 (“SPECIFIC INHIBITORS OF METHIONYL-TRNA SYNTHETASE”), published in 2015.

Research Status

In 2017, the TSRL-University of Washington team was awarded a three-year, $3,000,000 Direct-to-Phase II Small Business Innovation Research (SBIR) grant (#R44AI134190) from the National Institute of Allergy & Infectious Diseases (NIAID) of the National Institute of Health (NIH). Under this program, pre-lead candidates are optimized with a proprietary screening cascade focusing on improving three primary parameters. They are subsequently tested in TSRL's in vivo laboratories. The first goal is to increase metabolic half-life and allow for a once-a-day dosing. The second goal is to further suppress the potential for the emergence resistance, and the third is to establish an initial preclinical safety profile in preparation for an Investigational New Drug submission.

Antibiotics for Drug-Resistant Bacterial Infections

Methicillin- and Vancomycin-Resistant Staphylococcus Aureus (MRSA/VRSA)

Overview: MRSA and VRSA are strains of Staphylococcus aureus, a gram-positive bacterium that causes hundreds of thousands of infections per year in the United States. These clinically significant strains of Staphylococcus have developed resistance to beta-lactam antibiotics like penicillins and cephalosporins. Some strains have emerging resistance to newer antibiotics like linezolid, daptomycin, and tigecycline. For MRSA, the first line of treatment is the glycopeptide antibiotic vancomycin, which can be expensive and time consuming to administer. Moreover, many clinicians believe that the efficacy of vancomycin against MRSA is inferior to that of beta-lactam antibiotics against methicillin-susceptible Staphylococcus aureus. Several newly discovered strains of VRSA show antibiotic resistance to vancomycin and teicoplanin. 

Currently, fifth generation cephalosporins are used in the treatment of MRSA but they hold much smaller market share compared to generics like vanvomycin and teicoplanin (latter approved in EU). Coagulase-negative staphylococci have flourished in nosocomial environments where broad-spectrum cephalosporins have been used and glycopeptide-resistant enterococci and S. aureus have also emerged. To combat this emerging resistance, the United States, under the Generating Antibiotics Incentives Now Act (GAIN Act), has developed a shortened regulatory and review process for Qualified Infectious Disease Products (QIDPs) for antibiotics and antifungals.

Potential Regulatory Benefits: Qualified Infectious Disease Product Exclusivity, Fast-Track, Accelerated Review.

Market: The global MRSA therapeutics market stood at $1.45 billion in 2006, which then grew at a compound annual growth rate (CAGR) of 12.9% to reach $2.7 billion in 2011. The market is expected to grow at a CAGR of 3.4% over the next eight years to reach $3.5 billion by 2019. A first in class, extended spectrum antibiotic would provide another route to combat emerging resistance across a wide range of severe gram-positive infections and potentially peak at $450 million per year in global sales [6].

References:

[1] Zhang Z, Koh CY, Ranade RM, Shibata S, Gillespie JR, Hulverson MA, Nguyen J, Pendem N, Gelb MH, Verlinde CL, Hol WG, Buckner FS, and Fan E. 2016. 5-Fluoro-imidazo[4,5-b]pyridine is a privileged fragment that conveys bioavailability to potent trypanosomal methionyl-tRNA synthetase inhibitors. ACS Infect.Dis. 2:399-404.