A new antibiotic blocked lipopolysaccharide incorporation into the outer cell membrane
Swiss scientists have synthesized an antibiotic active against carbapenem-resistant Acinetobacter baumannii. They identified and optimized a molecule with a macrocyclic peptide - zosurabalpin - that blocks the transport of bacterial lipopolysaccharide from the inner membrane to its destination in the outer membrane of the bacterial cell by inhibiting the LptB2FGC complex. As reported in the journal Nature, the potential drug tackled the infection both in vitro and in mouse models.
Effective treatment of bacterial infections is considered to be the backbone of modern healthcare, which enables the realization of complex medical technologies: for example, transplantation, chemotherapy and various surgical interventions. Therefore, antibiotic-resistant bacterial infections pose a global threat to public health, and their increasing numbers have been referred to as a "silent pandemic" that undermines the safety of routine medical interventions and increases mortality worldwide.
Among antibiotic-resistant microorganisms, the most interesting is Acinetobacter baumannii, which is considered a critical and urgent threat by the World Health Organization and the U.S. Centers for Disease Control and Prevention. This opportunistic pathogen commonly causes hospital-acquired pneumonia and bloodstream infections. Its rapid accumulation of resistance mechanisms to several classes of antibiotics (including carbapenems) makes it an extremely dangerous complication of hospitalization.
A team of scientists led by Michael Lobritz and Kenneth Bradley of Roche Innovation Center analyzed the structure of 44985 macrocyclic peptides to find a tripeptide subunit with a diphenyl sulfide bond closing the ring. They identified a molecule, RO7075573, that was effective against A. baumannii in vitro but caused adverse reactions in mice. Optimization of the molecule using zwitter ions allowed them to secure the molecule and select the optimal dose to treat the mice. The final molecule was named zosurabalpin (zosurabalpin).
Bacteriologic analysis with whole-genome sequencing of individual colonies showed that zosurabalpin blocks the intramembrane LptB2FGC complex in Gram-negative bacteria, which transports lipopolysaccharides to the outer cell membrane. In mouse models, the molecule effectively fought the infection of resistant Acinetobacter baumannii, while the scientists did not find mechanisms by which the bacterium would become resistant to this substance. However, it turned out that zosurabalpin is specifically active only with A. baumannii.
American colleagues Lobritz and Bennett Daniel Kahne (Daniel Kahne) and Andrew Kruse (Andrew Kruse) from Harvard University further expanded knowledge about the mechanism of action zosurabalpin. Thus, they found that the molecule interacts with the complex LptB2FGC only when it is associated with lipopolysaccharide. And the reason for the specificity for A. baumannii should be considered the fact that the amino acid sequences of Lpt proteins have poor evolutionary conservation among other bacteria.
Overall, these data show that zosurabalpin can be considered as a candidate antibiotic effective against Acinetobacterium baumannii. Further research will focus on the safety profile in animals, and then doctors will conduct clinical trials to evaluate the drug's efficacy in humans.