Investigational Antibiotic Shows Broad Activity Against Resistant Gram-Negative Pathogens

By Gina Shaw

Original Source: FPI-2119 investigational antibiotic

A novel antibiotic that targets penicillin-binding proteins (PBPs) without relying on a beta-lactam scaffold demonstrated broad in-vitro activity, bactericidal effects, low resistance selection, and encouraging in-vivo efficacy across a series of preclinical studies presented at the inaugural Interdisciplinary Meeting on Antimicrobial Resistance and Innovation, in Las Vegas, on Jan. 29, 2026.

Across four related posters, investigators reported new data on FPI-2119, a lactivicin-derived, non–beta-lactam PBP inactivator being developed by Fedora Pharmaceuticals as a potential treatment for multidrug-resistant gram-negative infections (posters TOPIC7-THURS-245, -252, -254, and -255).

A Distinct Structure

Karen Bush, PhD, a professor of practice emerita in biology at Indiana University, in Indianapolis, and a leading authority on beta-lactamases and resistance mechanisms, presented data examining FPI-2119’s bactericidal activity and its low propensity to select for resistance in Enterobacterales. Although FPI-2119 targets PBPs, it is structurally distinct from beta-lactam antibiotics, a feature that may help it avoid some of the resistance pathways that undermine existing agents.

“One of the questions that always arises with new compounds that are related to beta-lactams is whether they will select for high levels of beta-lactamase,” Dr. Bush told Infectious Disease Special Edition. “That’s been a major problem historically.”

To address that concern, Dr. Bush and colleagues evaluated resistance frequency and beta-lactamase activity in Escherichia coli and an inducible Enterobacter cloacae strain. In single-step resistance selection experiments, FPI-2119 demonstrated frequencies of resistance comparable to standard beta-lactams. Importantly, persister isolates—susceptible bacteria that survive lethal doses of antibiotics—selected during time-kill and resistance studies did not show increased basal beta-lactamase activity.

“We looked at four different persisters, and all of them had essentially the same beta-lactamase activity as the wild type,” Dr. Bush said. “So we’re not selecting for overproduced beta-lactamases.”

FPI-2119 also demonstrated concentration- and time-dependent bactericidal activity. While some regrowth was observed at lower concentrations after prolonged exposure, Dr. Bush noted that isolates recovered under those conditions exhibited impaired fitness.

“The strains that were selected had impaired growth rates,” she said. “They either grew more slowly in log phase or never reached the same stationary-phase density as the wild type.”

Taken together, those findings suggest that while bacterial survival can occur under suboptimal exposure, the compound does not appear to readily drive stable, high-level resistance. “Overall, it looks like a pretty decent compound,” Dr. Bush said. “I’d like to see it further developed.”

A Clean Dose-Response

Immediately downstream of those microbiological findings, in-vivo efficacy data presented by Lynn Miesel, PhD, the senior technical director for Pharmacy Discovery Services, in New York City, demonstrated that FPI-2119 translated its in-vitro potency into meaningful activity in animal infection models.

“We had two types of murine models, one for bloodstream infection and one for pneumonia,” Dr. Miesel said. In a Klebsiella pneumoniae bacteremia model, a single intravenous dose of FPI-2119 produced a dose-responsive reduction in bacterial burden. “The single administration caused a very nice, clean dose-responsive reduction in bacterial counts in heart, lung, and kidney tissue,” she said, with similar effects across all three organs, suggesting good tissue penetration.

In a neutropenic lung infection model, repeated dosing further supported the compound’s activity. “At 40 mg per kg, we saw bacteriostasis,” Dr. Miesel said. “And at 160 mg per kg, there was a two-log kill.”

Activity in MDR Pathogens

Additional posters rounded out the preclinical profile. Sameeh Salama, PhD, the chief scientific officer at Fedora, reported that FPI-2119 retained potent in-vitro activity against a wide range of multidrug-resistant gram-negative pathogens, including carbapenem-resistant Pseudomonas aeruginosa, Acinetobacter baumannii, and Enterobacterales harboring multiple beta-lactamase classes. The compound also remained active against isolates resistant to colistin and cefiderocol (Fetroja, Shionogi).

Finally, mechanistic studies presented by Alaa Sayed, PhD, of St. Jude Children’s Research Hospital, demonstrated that FPI-2119 binds multiple essential PBPs—PBP1a, 1b, 2, and 3—in E. coli and Klebsiella pneumoniae. Microscopy revealed filamentation patterns consistent with PBP3 inhibition, supporting a multi-target mechanism that may help limit the emergence of resistance.

While the compound remains in early development, the four studies position FPI-2119 as a mechanistically novel antibacterial candidate with activity against some of the most challenging gram-negative pathogens.

Dr. Bush reported financial relationships with Asieris, BMS, Fedora, Johnson & Johnson, Lilly, Merck, Pfizer, and Shionogi. Dr. Salama is the chief scientific officer of Fedora. The research was supported by Fedora.