Novel antibiotic class promising against invasive infections caused by carbapenem-resistant Acinetobacter: Study

In the research published in Nature, Claudia Zampaloni, Roche Innovation Center Basel, F. Hoffmann-La Roche, Basel, Switzerland, and colleagues described the identification and optimization of tethered macrocyclic peptide (MCP) antibiotics. These antibiotics target carbapenem-resistant Acinetobacter baumannii (CRAB) by inhibiting one of the building blocks of the bacterium's hard-to-penetrate outer wall.

They further found the high effectiveness of a clinical candidate from this class called zosurabalpin (RG6006) at treating CRAB isolates both in vitro and in mouse models of infection.

"This chemical class is a promising treatment paradigm for patients with invasive infections due to CRAB, for whom current treatment options are inadequate," the researchers wrote. They additionally identified LptB2FGC as a tractable target for antimicrobial drug development.

Carbapenem-resistant Acinetobacter baumannii has emerged as a major global pathogen having limited treatment options. In patients over 50 years old, no new antibiotic chemical class with activity against A. baumannii has been reached. Dr. Zampaloni and colleagues report the identification and optimization of tethered macrocyclic peptide antibiotics with potent antibacterial activity against CRAB.

CRAB is considered one of the leading antibiotic resistance threats by both the Centers for Disease Control and Prevention and the World Health Organization and a priority for antibiotic development, with mortality estimates for invasive infections ranging from 40% to 60% and limited treatment options.

Beyond carbapenems, CRAB infections are often resistant to multiple other antibiotics, leaving patients with limited treatment options. However, A baumannii has a tough outer membrane (like other gram-negative bacterial pathogens) blocking the entry of most antibiotics, making it a difficult target for antibiotic developers.

Collectively, these data support the hypothesis that antibacterial activity is mediated through a new target.

"MCP displayed a highly similar phenotypic profile across several tested compounds while differentiating from other known antibiotic classes," they wrote. "Taken together, these data support the hypothesis that antibacterial activity is mediated through a new target."

According to the researchers, tethered MCPs, identified through the screening of about 45,000 compounds, solve the problem by blocking the transport of lipopolysaccharide (LPS) from the inner membrane to the outer membrane, which is requisite for the formation of an outer membrane and antibiotic resistance.

A process called bacterial phenotypic fingerprint profiling revealed that a cluster of the identified MCP shared this mode of action.

"Collectively, these data demonstrate the zosurabalpin's potential as an antibiotic and human clinical trials have been initiated to further develop this compound to provide a treatment option for invasive infections caused by CRAB," the researchers wrote.

Reference:

Zampaloni, C., Mattei, P., Bleicher, K., Winther, L., Thäte, C., Bucher, C., Adam, J., Alanine, A., Amrein, K. E., Baidin, V., Bieniossek, C., Bissantz, C., Boess, F., Cantrill, C., Clairfeuille, T., Dey, F., Di Giorgio, P., Du Castel, P., Dylus, D., . . . Bradley, K. A. (2024). A novel antibiotic class targeting the lipopolysaccharide transporter. Nature, 1-6. https://doi.org/10.1038/s41586-023-06873-0