Our robust pipeline consists of clinical and pre-clinical pathogen-targeted small-molecule antibacterials for the treatment of multidrug-resistant Gram-negative bacteria.
The pipeline includes programs for differentiated medicines to treat serious multidrug-resistant Gram-negative infections, such as Pseudomonas aeruginosa, Acinetobacter baumanii, carbapenem-resistant Enterobacteriaceae, and Neisseria gonorrhoeae.
ETX2514 is a broad-spectrum and potent inhibitor of class A, C, and D beta-lactamases. Acinetobacter baumannii is a Gram-negative bacterium that causes severe infections which are associated with high mortality. A. baumannii infections are frequently multi-drug resistant and there is an urgent need to identify new agents to treat these infections. Sulbactam is a beta-lactam antimicrobial which has intrinsic activity against A. baumannii, but beta-lactamase-mediated resistance to sulbactam is now widespread. In preclinical studies, ETX2514 restores sulbactam’s antimicrobial activity. Entasis Therapeutics is developing the combination of sulbactam and ETX2514 for the treatment of severe A. baumannii infections.
At the American Society for Microbiology (ASM) Microbe 2016 conference, Entasis scientists presented the activity of ETX2514 against multiple beta-lactamases and penicillin binding proteins, demonstrating potent inhibition of Class A, C and a broad spectrum of Class D beta-lactamases, important targets in the prevention of bacterial resistance. The results demonstrate restoration of antimicrobial activity in combination with various beta-lactams against Gram-negative, multi-drug resistant (MDR) pathogens, including against MDR and extensively drug resistant (XDR) Acinetobacter baumannii, a significant public health concern which is classified as a serious threat pathogen in the Centers for Disease Control and Prevention’s “Antibiotic Resistance Threats” report.
Entasis scientists also presented the further evaluation of the therapeutic potential of ETX2514 and sulbactam in animal infection models of MDR A. baumannii. Different dosing regimens of these agents were investigated to identify appropriate concentrations of both ETX2514 and sulbactam required for robust antimicrobial efficacy. Overall results suggest that the administration of sulbactam in combination with ETX2514 has the potential to be an effective treatment for infections caused by MDR and XDR A. baumannii.
Entasis presentations on ETX2514 can be seen here.
ETX0282 is an orally available, broad spectrum inhibitor of class A and C beta-lactamases. Entasis is developing ETX0282 in combination with cefpodoxime, an orally available cephalosporin approved for treating a variety of bacterial infections but lacking in efficacy due to beta-lactamase mediated resistance. In preclinical studies, ETX0282 restores cefpodoxime’s antimicrobial activity against a variety of pathogens including Enterobacteriaceae resistant to fluoroquinolones, cephalosporins, and carbapenems. Entasis is initially developing ETX0282CPDP, the combination of ETX0282 and cefpodoxime, for the treatment of infections caused by Enterobacteriaceae. ETX0282CPDP is powered by CARB-X.
Zoliflodacin (ETX0914) is a novel oral antibiotic for the treatment of uncomplicated gonorrhea and the first of a novel class of molecules to be developed for this indication. Uncomplicated gonorrhea is becoming increasingly difficult to treat as the Neisseria gonorrhoeae bacterium has developed resistance to successive classes of antibiotics. There are currently few oral treatment options and the US Centers for Disease Control and Prevention has recently designated N. gonorrhoeae an urgent public health threat that requires aggressive action. N. gonorrhoeae has developed resistance to all classes of antimicrobials previously recommended for treatment of uncomplicated gonorrhea, leaving only one injectable cephalosporin, ceftriaxone, as a recommended first-line therapy. Uncomplicated gonorrhea infections carry high morbidity, enhance transmission of other sexually transmitted diseases and are highly stigmatized. Published studies have demonstrated the potent in vitro activity of zoliflodacin against N. gonorrhoeae, including isolates resistant to fluoroquinolones and extended spectrum cephalosporins. A randomized, open-label Phase 2 study of oral ETX0914 (formerly AZD0914) was completed in December of 2015 in individuals with uncomplicated gonorrhea. ETX0914 has been designated a Qualified Infectious Disease Product (QIDP) by the U.S. Food and Drug Administration and awarded a Fast Track status. In July 2017, Entasis partnered with the Global Antibiotic Research and Development Partnership (GARDP) to co-develop zoliflodacin through Phase 3. In the partnership, Entasis retains all commercial rights to zoliflodacin in high-income territories while GARDP receives commerical rights in low- and middle-income markets.
Our drug discovery and preclinical platform is focused on developing novel antibacterials targeting serious Gram-negative infections. Pneumonia, infections of the blood, urinary tract infections (UTI) and infections following surgery can lead to severe illness and death. Strains of bacteria are emerging which are untreatable with antibiotics currently recommended as the standard of care. Our unique insights of the structure and function of bacterial ß-lactamases, a class of enzymes that is frequently responsible for antibiotic resistance, have enabled us to discover new antibiotics with activity against highly resistant organisms, such as Acinetobacter baumanii, Pseudomonas aeruginosa, and drug-resistant Enterobacteriaceae. Our approach uses genetic tools, molecular dynamics simulations and modeling in a highly directed, focused way to design new medicines with improved efficacy against these very challenging pathogens.