Cutting off avenues of ESKAPE

Novel antibiotics from Melinta show in-vitro potential against resistant bacteria

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NEW HAVEN, Conn.—Melinta Therapeutics has released an update on its ESKAPE Pathogen Program, presenting two posters at the Interscience Conference on Antimicrobial Agents and Chemotherapy on its RX-P873 molecule that demonstrated its activity against a range of Gram-negative bacteria, including multidrug resistant strains and those designated on the U.S. Center for Disease Control and Prevention’s (CDC) list of urgent threats.
The ESKAPE pathogens consist of Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumonia, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species and Escherichia coli. These resistant bacteria are the most difficult to treat, and 66 percent of all hospital infections are the result of these pathogens. Drug-resistant bacteria have, in recent years, been named one of the leading health concerns in the United States. According to the CDC, approximately 2 million people in the United States develop infections caused by resistant bacteria, and more than 23,000 people die each year from antibiotic-resistant infections.
Melinta’s ESKAPE Pathogen Program combines the company’s crystallography and computational chemistry experience to generate new classes of antibiotics and new molecules to treat extensively drug resistant and multidrug resistant bacteria. As noted on the company’s website, “Melinta researchers generated three unique molecular scaffolds with high binding affinity, low off-target effect and broad-spectrum antibiotic properties. Compounds based on one of these molecular scaffolds—the pyrrolocytosines—have shown in-vitro activity and preclinical efficacy against multidrug resistant Gram-negative and Gram-positive strains of bacteria known to cause complicated urinary tract infections, skin and lung infections, as well as sepsis.” From Melinta’s three novel classes of antibiotics, more than 2,500 molecules have been produced, and Melinta is completing preclinical work to advance the most promising leads into Phase 1 clinical studies.
RX-P873 falls within the pyrrolocytosine class of compounds. It was specifically tested against Gram-negative species of bacteria, including 10 from the Enterobacteriaceae family, as well as Pseudomonas aeruginosa and Acinetobacter baumannii. The compound demonstrated potent activity against the Enterobacteriaceae family, as it inhibited more than 97 percent of isolates. RX-P873 was also shown to be highly active against P. aeruginosa, including strains that are resistant to ceftazidime or meropenem, and was the most active agent tested against A. baumannii; in that area, it displayed greater activity than colistin.
“Melinta’s discovery team employs a highly disciplined structure-based design approach that we believe can deliver both next-generation antibiotics and completely new classes, which can be fine-tuned to address current and emerging threats,” Dr. Erin Duffy, chief scientific officer of Melinta, said in a news release. “As seen in the above studies, RX-P873 shows high and consistent in-vitro potency across a variety of Gram-negative pathogens, including those commonly associated with complicated urinary tract infections, complicated intra-abdominal infections and lung infections. We are encouraged by these early-stage results and look forward to completing our preclinical efforts and advancing molecules from the ESKAPE Pathogen Program into the clinic.”
Melinta also recently shared news on one of its late-stage antibiotics, delafloxacin, a novel fluoroquinolone compound in Phase 3 development for the treatment of acute bacterial skin and skin structure infections (ABSSSI) and uncomplicated gonorrhea. The U.S. Food and Drug Administration has designated delafloxacin as a qualified infectious disease product for ABSSSI, uncomplicated gonorrhea and community-acquired bacterial pneumonia.
On Sept. 6, Melinta announced, along with Hartford Hospital, that in-vitro results from a recent study highlighted delafloxacin’s activity in low-pH environments, which are indicative of infection sites. When tested in samples from patients suspected to have urinary tract infections (UTI), delafloxacin demonstrated activity against E. coli and K. pneumoniae, both of which are associated with complicated UTIs. Two days later, the company shared results from in-vitro studies supporting delafloxacin’s potential in targeting Neisseria gonorrhoeae, the organism that causes gonorrhea. This pathogen has developed resistance to all classes of antimicrobials that have previously been recommended to treat gonorrhea, Melinta noted in a press release. In comparison, delafloxacin demonstrated activity against all 50 of the ciprofloxacin-resistant isolates tested in a study with University of Washington collaborators. In a separate in-vitro study, the compound proved to be more rapidly bactericidal against ciprofloxacin-susceptible and -resistant N. gonorrhoeae strains than ceftriaxone, the recommended first-line treatment for gonorrhea.

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