Swiss pharmaceutical firm Roche has advanced its antibiotic candidate, zosurabalpin, into Phase 3 clinical trials, representing a potential landmark in the fight against Gram-negative bacterial infections. Targeting carbapenem-resistant Acinetobacter baumannii, the drug could mark the first approval of a novel antibiotic class in more than 50 years.
Zosurabalpin, a tethered macrocyclic peptide developed in collaboration with Harvard University, disrupts the outer lipopolysaccharide membrane essential for bacterial survival. Early-stage studies demonstrated favourable safety and pharmacokinetic profiles, while animal models of lung and thigh infections caused by CRAB confirmed its therapeutic potential. Roche anticipates enrolling approximately 400 hospitalised patients worldwide in the upcoming trial round, with the aim of comparing zosurabalpin directly against current standard-of-care antibiotics.
The urgency of this development is underscored by CRAB’s classification by the US Centers for Disease Control and Prevention as an “urgent threat” and by the World Health Organization as a high priority pathogen. Infection fatality rates hover around 40–60%, particularly among immunocompromised patients such as those in intensive care. Existing antibiotics are often ineffective due to CRAB’s robust outer membranes that thwart drug penetration.
Phase 3 trials are scheduled to begin late this year or in early 2026, spanning over 100 global sites and aiming for regulatory submission by the decade’s end. Roche executives emphasise that approval would not only address a dire clinical need but also serve as a catalyst for renewed antibiotic research, especially against Gram-negative organisms. “Finding new classes is very hard,” noted Michael Lobritz, Roche’s global head of infectious diseases; approval could lay groundwork for future innovation.
Roche has previously stepped back from antibiotic R&D, but a reinvestment around ten years ago has now yielded zosurabalpin. The firm is simultaneously exploring additional novel compounds, including a LepB inhibitor targeting carbapenem-resistant Gram-negative pathogens in urinary tract infections.
Efforts to restore antibiotic pipelines have gained traction from policymakers. The UK introduced a subscription-style payment model to support antimicrobial development, decoupling revenue from volume to ensure steady returns. The US is now considering similar incentives. Such frameworks aim to overcome financial disincentives that have plagued the industry, contributing to the closure of many smaller biotechs focusing on antibiotics.
Meanwhile, complementary research is underway. A novel molecule named lariocidin was identified from soil bacteria by scientists at McMaster University. It targets the bacterial ribosome through a distinctive lasso-peptide structure but remains in preclinical stages. Similarly, researchers at MIT and McMaster have used artificial-intelligence methods to develop abaucin, a narrow-spectrum compound effective in killing CRAB. Both discoveries offer hope for expanding the antibiotic pipeline beyond zosurabalpin.
Zosurabalpin’s mechanism of action—from inhibiting lipopolysaccharide transport to compromising the bacterial envelope—distinguishes it from older therapies, which have often been broad-spectrum and prone to fostering resistance. By contrast, this new agent is narrow-spectrum, tailored to CRAB and avoiding pre-existing resistance mechanisms.
The evolving antibiotic landscape now features roughly 20 candidates in clinical development for high-priority pathogens, though historical attrition rates remain troubling. Financial instability has led to the collapse of several promising antibiotic-focused firms, exemplified by Achaogen’s bankruptcy in 2019 shortly after FDA approval of plazomicin.
In light of these challenges, zosurabalpin represents a critical test case: its success could prove the viability of targeted, high-impact antibiotic development supported by improved economic incentives. As Roche and its collaborators gear up for the pivotal Phase 3 trial, global health advocates view the outcome not only as a potential therapeutic breakthrough, but as a signal of renewed momentum in a sector long plagued by stagnation.
