The bacteria Acinetobacter baumannii may seem harmless at first glance. It’s found throughout nature in soil and water, and it rarely makes people sick.1 However, for people with weakened immune systems who require antibiotics to fight off an infection, A. baumannii is a major threat. The species is crafty, though, and quickly evolves its genetic defenses to destroy many common antibiotics, which has left only a handful of effective treatments for the most vulnerable patients.
The antibiotic pipeline has been clogged for decades; scientists discovered the last new family of antibiotics effective against A. baumannii 50 years ago. Now, scientists have found a promising new candidate. In work published in Nature, they described a new class of antibiotics that sneaks past bacterial defenses by interfering with a key membrane protein. These carefully engineered molecules may one day treat challenging Carbapenem-resistant A. baumannii, or CRAB, infections.2 “The motivation is really the unmet medical need in the space and the rise of multidrug resistance,” said Kenneth Bradley, a microbiologist at Roche and author of the study.
Around ten years ago, scientists at Roche started exploring a burgeoning class of drug candidates called macrocyclic peptides, which researchers have explored as treatments for everything from infections to cardiovascular disease.3,4 Another company, Tranzyme Pharma, previously tested the bacteria-killing ability of more than 40,000 macrocyclic peptides.5 Using this data, the Roche scientists honed in on one particular molecule that seemed especially suited to killing CRAB bacteria.
“By starting with a phenotypic screen, you're starting in a chemical space that at least has that ability to penetrate the [bacterial] envelope and get to the target, wherever it may reside,” Bradley said. “This overcomes some of the hurdles that were well documented in the literature from earlier screens and antibacterials.”
The molecule was promising, but Bradley and his team thought that they could make it even better, so they tweaked it. This resulted in an antibiotic that was even more potent against CRAB. But when they tested it in rats, it was too potent; many of the rats treated with the antibiotic died. Bradley’s team realized that they needed to modify the molecule even further.
Infectious disease, especially [when caused by] drug-resistant bacteria, is different than most other indications in that you need a continual supply of new, different drugs because the bacteria are evolving.
- Paul Hergenrother, University of Illinois Urbana-Champaign
With a safer and more effective molecule in hand, the researchers set out to discover how the molecule killed bacteria. They sequenced the genomes of bacteria that successfully and unsuccessfully evaded the antibiotic and searched for mutations unique to the victorious bugs. The researchers reasoned that these mutations likely fortified genes that encoded critical targets for the antibiotic. With further biochemical studies done in collaboration with researchers at Harvard University, they pinpointed the antibiotic molecule’s target: the lipopolysaccharide (LPS) transport pathway.6 LPS is typically found in large amounts on the cell surface of Gram-negative bacteria, a class that includes A. baumannii, but it has to move there from inside the cell. When that process is interrupted, LPS accumulates inside the bacterium and becomes toxic.
The final version of the molecule, dubbed zosurabalpin, is the only antibiotic to target LPS transport. Bradley said that having a novel mechanism is important, “not because of the word ‘novel’ but because it has the potential to overcome pre-existing mechanisms of resistance that are already disseminated in bacteria.”
The researchers found that zosurabalpin outperformed existing antibiotics at stemming the growth of hard-to-treat bacteria, and the molecule also successfully fought CRAB infections in a variety of mouse models. Zosurabalpin is unique among antibiotics because it is a man-made chemical, rather than a natural product of bacteria or fungi, such as penicillin. According to Paul Hergenrother, a chemist at the University of Illinois Urbana-Champaign who was not involved in the study, the fact that the molecule is synthetic doesn’t mean that bacteria won’t develop resistance.7
“Infectious disease, especially [when caused by] drug-resistant bacteria, is different than most other indications in that you need a continual supply of new, different drugs because the bacteria are evolving,” Hergenrother said. “Kudos to Roche for staying in the game.”
Roche began clinical trials of zosurabalpin in 2020 to assess its safety. Preliminary results revealed only minor side effects in healthy participants.8 While there’s still a long path to Food and Drug Administration approval for the drug, Hergenrother is optimistic that the field will see approvals for new antibiotics soon. “There's a reasonable supply of candidates,” he said. “There are some really creative approaches and other really promising antibiotics.”
For scientists searching for new antibiotics, Bradley had some words of caution. “It's easy to find compounds that kill bacteria. It's a bit harder to make those molecules also safe and efficacious,” Bradley said.
- Peleg AY, et al. Acinetobacter baumannii: Emergence of a successful pathogen. Clin Microbiol Rev. 2008;21(3):538-582.
- Zampaloni C, et al. A novel antibiotic class targeting the lipopolysaccharide transporter. Nature. 2024;625(7995):566-571.
- Zorzi A, et al. Cyclic peptide therapeutics: past, present and future. Curr Opin Chem Biol. 2017;38:24-29.
- Johns DG, et al. Orally bioavailable macrocyclic peptide that inhibits binding of PCSK9 to the low density lipoprotein receptor. Circulation. 2023;148(2):144-158.
- Marsault E, et al. Efficient parallel synthesis of macrocyclic peptidomimetics. Bioorg Med Chem Lett. 2008;18(16):4731-5.
- Pahil KS, et al. A new antibiotic traps lipopolysaccharide in its intermembrane transporter. Nature. 2024;625(7995):572-577.
- Larsson DGJ, Flach C. Antibiotic resistance in the environment. Nat Rev Microbiol. 2022;20(5):257-269.
- Guenther A, et al. 2126. Safety, tolerability, and pharmacokinetics (PK) in healthy participants following single dose administration of Zosurabalpin, a novel pathogen-specific antibiotic for the treatment of serious Acinetobacter infections. Open Forum Infect Dis. 2023;10(Suppl 2):ofad500.1749.
