Crestone
Developing Antibiotics that Break the Bacterial Growth and Resistance Cycle

Crestone, a clinical-stage biopharmaceutical company in Boulder, CO, is one of the largest corporate recipients of funds from NIAID (National Institute of Allergy and Infectious Diseases) to develop antibiotics addressing areas of unmet medical need. At present, the company’s R&D pipeline includes three funded programs at various levels of maturity with the aim to develop novel mechanism of action, smallmolecule drugs that break the cycle of bacterial growth and resistance. Molecules currently in the Crestone pipeline that tackles severe bacterial infections are CRS3123 for the treatment of C. difficile infection, CRS0540 to attack Grampositive bacteria, and CRS0393 to address nontuberculous mycobacteria (NTM) and tuberculosis (TB).

“Going after molecular targets that are, as of yet, unexploited in bacteria is our specialty. Our focus is to develop novel mechanism of action agents that get us ahead of increasing antimicrobial resistance (AMR) to existing antibiotics,” says Urs Ochsner, Founder and CEO of Crestone.

To break the disease burden caused by Clostridium difficile infection (CDI), CRS3123 inhibits the C. difficile (C. diff) bacteria in the gut from synthesizing proteins, inhibiting bacterial growth and preventing it from making the toxins and spores that cause many of the negative effects of CDI. Being a narrow-spectrum antibiotic, CRS3123 selectively targets and inhibits the toxicity produced by C. diff, which may lead to a much faster resolution of symptoms and fewer chances for recurrence. Furthermore, CRS3123 does not disrupt normal gut microbiota compared to the existing CDI therapies available in the market.

CRS3123 is also being explored as a gut microbiotamodulating agent for other diseases. For instance, diseases caused by bacterial toxins, including some that cross the blood-brain barrier, have been proven to affect the central nervous system. With studies establishing the connection between a healthy gut microbial flora and autism, Crestone is planning a proof-of-concept study of CRS3123 to improve gastrointestinal and/or behavioral symptoms in adolescents living with autism.

CRS0540 inhibits bacterial DNA replication by targeting PolC, the polymerase responsible for genome replication in Gram-positive bacteria.

By hindering this novel bacterial target, CRS0540 can inhibit bacteria such as methicillinresistant Staphylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae (PRSP), and vancomycinresistant enterococci (VRE), thereby circumventing their antibiotic resistance, and killing the pathogens. CRS0540 is currently in late-stage pre-clinical development. Importantly, CRS0540 is being developed both as an intravenous formulation but also as a pill or tablet that patients can take at home, permitting them to be discharged from hospital sooner.

Targeting the protein essential for cell wall synthesis, Crestone is currently developing an anti-mycobacterial agent, CRS0393, which shows high potency against all tested mycobacteria, including multidrug-resistant strains. Additionally, the targeted protein is unique to mycobacteria, allowing the small-molecule drug to have a narrow spectrum of activity. CRS0393 has potential as a novel mechanism of action drug to be used against nontuberculous mycobacteria (NTM) and tuberculosis (TB) that cause chronic respiratory infections which are difficult to treat and require multiple drugs that patients find difficult to tolerate. CRS0393 is currently in preclinical development, showing positive results in animal models and entering IND-enabling studies as an oral and/or inhaled agent.

Since the late 1990s, antibiotics released in the market are variations of the existing drugs. The cost of developing new drugs is the root cause for the lack of innovations in the industry, with studies reporting that global pharmaceutical companies had the third-highest R&D intensity in 2019, amounting to billions of dollars. Another factor is their inability to break even when marketing novel antibiotics, due to low prices and competition from cheap, legacy antibiotics that may not be as effective due to resistance.

To overcome this hurdle that has the potential to impact society at large, NIAID has funded Crestone and other companies conducting antibiotic research and development. Crestone’s focus on addressing areas of unmet medical needs goes beyond clinical trials, and R&D. Crestone continues to raise awareness of antimicrobial resistance and related concerns through social media efforts, conversations with local legislators, and partnership with patient advocacy organizations like The Peggy Lillis Foundation and C Diff Foundation. These factors, coupled with Crestone’s team of passionate experts, are making a significant difference in developing novel treatments to fight against infections of antibiotic-resistant pathogens that pose an ever-increasing threat to humankind.