Hope for narrow-spectrum, pathogen-specific antimicrobials that minimize collateral damage to the microbiome
Two interesting 2024 companion papers were published in Nature: A novel antibiotic class targeting the lipopolysaccharide transporter - PubMed (nih.gov) and A new antibiotic traps lipopolysaccharide in its intermembrane transporter - PubMed (nih.gov). These papers are on a recent antimicrobial drug screening campaign by Roche that identified macrocyclic compounds with narrow-spectrum pathogen-specific activity against the Gram-negative bacterium Acinetobacter baumannii. The authors discovered their compounds block lipopolysaccharide (LPS) transport from the inner membrane to the outer membrane, and cryo-EM reconstructions show structural differences in the LPS transporter may be useful for generating next-gen narrow-spectrum antimicrobials against other Gram-negative pathogens (e.g., Pseudomonas, Klebsiella, etc). The authors find that the resistance mutations that promote in vitro growth with the antimicrobial compound compromises virulence in vivo, providing optimism for the feasibility of deploying their compound in the clinic.
There are several other interesting aspects about the story. A deeper dive into the history of the macrocycles Roche screened shows they were originally made 25 years ago by a company called Tranzyme Pharmaceuticals with aspirations to treat GI disorders. Tranzyme had several rounds of funding but, shortly after their last round of funding in 2010, they brought on George Abercrombie (former Roche exec) to serve on their board of directors in 2011. Two years later Tranzyme merges with Ocera Therapeutics in 2013 to deploy their macrocycles against liver disease. Four years later in 2017 Tranzyme/Ocera get acquired by Mallinckrodt to keep working on the liver disease after a failed clinical trial (no statistically significant improvement over placebo). In 2020 Roche initiated a Phase I safety trial in healthy people of a macrocycle that was pulled out of the Tranzyme library (NCT04605718). One wonders if Abercrombie facilitated Roche access to the Tranzyme library! Then in 2022 Roche initiated a Phase I safety trial in critically ill people with bacterial infections of their macrocyclic compound (NCT05614895). One of the sites of the later safety trial is here in Kentucky at the University of Louisville, that is actively testing the compound published in the Nature papers! Compounds that were originally intended for GI and liver disease may provide the next big splash in antimicrobial drug discovery - something that is desperately needed.
Another interesting aspect is Extended Data figure 2 in the first companion paper. This figure shows a comparison of the macrocycles against ~1.5 million Roche compounds that have been screened against Gram-negative pathogens. A machine-learning algorithm comparing the relationship between compound MICs, cellular phenotypes when treated with compound, and the compound concentration that causes the phenotypes, calculates similarity scores and deduces the mechanism of action of compounds. This computational study shows the uniqueness of the macrocyles/targeting LPS transport, compared to everything Roche has screened previously. Although it will probably never happen, it would be interesting to mine their database to see how big the chemical space is for inhibitors that target the same cellular targets.
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Christopher Radka
Assistant Professor
University of Kentucky College of Medicine
Lexington KY
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