Novel antibiotic class shows promise against carbapenem-resistant Acinetobacter

Acinetobacter baumannii

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Scientists with Swiss drugmaker Roche say they have identified a novel class of antibiotics that target a highly drug-resistant and deadly bacterial pathogen.

In a paper published this week in Nature, researchers at Roche Innovation Center Basel describe the identification and optimization of tethered macrocyclic peptide (MCP) antibiotics, which 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 that a clinical candidate from this class called zosurabalpin (RG6006) was highly effective at treating CRAB isolates both in vitro and in mouse models of infection.

While human clinical trials for zosurabalpin are just starting, the researchers say the unique chemical structure and novel mode of action of MCPs represent a "promising treatment paradigm" for patients with invasive CRAB infections.

A tough target for antibiotic development

With mortality estimates for invasive infections ranging from 40% to 60% and limited treatment options, CRAB is considered one of the leading antibiotic resistance threats by both the World Health Organization and the Centers for Disease Control and Prevention and a priority for antibiotic development. Beyond carbapenems, CRAB infections are often resistant to multiple other antibiotics, leaving patients with limited treatment options.

But like other gram-negative bacterial pathogens, A baumannii has a tough outer membrane that blocks entry of most antibiotics, making it a difficult target for antibiotic developers.

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

The researchers say that tethered MCPs, which they identified through the screening of nearly 45,000 compounds, solve that problem by blocking the transport of lipopolysaccharide (LPS) from the inner membrane to the outer membrane, which is essential for outer membrane formation and antibiotic resistance. A process called bacterial phenotypic fingerprint profiling revealed that a cluster of the identified MCPs shared this mode of action.

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

In a companion paper in the same journal, researchers from Roche and Harvard Medical School further explore this mechanism and explain why the ability of MCPs to disrupt the LPS transport system is a significant discovery.

"Assembly of the outer membrane requires transport of LPS across a protein bridge that spans from the cytoplasmic membrane to the cell surface," they wrote. "Maintaining outer membrane integrity is essential for bacterial cell viability, and its disruption can increase susceptibility to other antibiotics."

One candidate stands out

While the screening produced several MCPs that showed potent activity against both susceptible and resistant A baumannii in lab and mouse experiments, zosurabalpin stood out because it was found to be better tolerated when infused intravenously into rats. Further analysis revealed that zosurabalpin's mechanism of action is inhibition of a component of the LPS transport system called the LptB2FGC complex.

Subsequent testing revealed that zosurabalpin was highly effective in lab tests against 129 human clinical CRAB isolates and in mice with lung and thigh infections caused by a pan–drug-resistant A baumannii clinical isolate.

"These data collectively demonstrate the potential of zosurabalpin as an antibiotic, and human clinical trials have been initiated to further develop this compound with the goal of providing a treatment option for invasive infections caused by CRAB," the researchers wrote.

Results from the initial clinical trials are expected later this year.

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