Woman researcher performing examination of bacterial culture plate
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A new antibiotic class that works against multidrug-resistant bacteria has been discovered, offering new opportunities to tackle these dangerous microbes.

The macrocyclic peptide zosurabalpin showed promising antibacterial activity against Carbapenem-resistant Acinetobacter baumannii (CRAB), according to two papers published in the journal Nature.

The Gram-negative bacteria is deemed an urgent threat by the U.S. Centers for Disease Control and Prevention and has also been classified as a priority 1 critical pathogen by the World Health Organization.

“The new molecule overcomes the existing drug-resistance mechanisms that the currently available antibiotics are failing to address,” said Kenneth Bradley, global head of infectious disease discovery at Roche pharma research & early development, which worked with Harvard researchers to establish the mechanism of action for the compound.

“With this significant breakthrough, zosurabalpin has the potential to address a major unmet need in the fight against antimicrobial resistance.”

Gram-negative bacteria are particularly difficult to kill because they are encased in both inner and outer membranes that are challenging for most antibiotics to cross. The cytoplasmic membrane is surrounded by an outer membrane containing lipopolysaccharide (LPS), which blocks the entry of most antibiotics.

Zosurabalpin traps this LPS during its transport to the outer membrane by inhibiting a complex of proteins called the LptB2FGC complex.

Specifically, the clinical candidate binds to both LPS and a transport complex that facilitates movement to its destination. The LPS transport complex is trapped in a substrate-bound state, which leaves it unable to move LPS and results in death of the bacterium.

A team led by Claudia Zampaloni, PhD, senior principal scientist in infectious diseases at Roche, initially examined around 45,000 tethered macrocyclic peptides, which have greater molecular weights than most antibiotics.

The researchers identified one that selectively killed A. baumannii, which was further honed for efficacy and tolerability using a new type of test based on blood-plasma compatibility, culminating in the discovery of zosurabalpin.

The drug was effective against more than 100 CRAB clinical samples tested in the lab and in multiple mouse infection models, including sepsis and thigh and lung infection induced by CRAB strains.

In another research article, Karanbir Pahil, PhD, from Harvard University, and colleagues use X-ray techniques to identify structures that show zosurabalpin engages LptB2FGC only when the complex is bound to LPS, indicating the importance of the latter for its action.

The basis for its specificity against A. baumannii lies in this protein complex, explaining why it is ineffective against other bacteria whose Lpt proteins may have different amino-acid sequences.

This previously unknown mode of antibiotic action suggests that pre-existing resistance is unlikely, note Morgan Gugger and Paul Hergenrother, PhD, both from the University of Illinois at Urbana-Champaign, in accompanying News and Views article.

They point out that the U.S. Food and Drug Administration has not approved any new classes of antibiotic for harmful Gram-negative bacteria in more than 50 years.

“Treatment options for CRAB infections continue to dwindle as mortality rates are rising, with some estimated death rates reaching approximately 50% for invasive infections,” they warn.

The commentators add that zosurabalpin might not have the damaging effect on normal gut microbes seen with most antibiotics,  given its high specificity for A. baumannii.

“The movement towards bacterium-specific antibiotics is a new development, and one that can be facilitated by diagnostics that can rapidly identify specific harmful bacteria in infected individuals,” they wrote.

“Given that zosurabalpin is already being tested in clinical trials, the future looks promising, with the possibility of a new antibiotic class being finally on the horizon for invasive CRAB infections.”

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