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Gram-negative bacterial infections are challenging to treat because the amphipathic lipopolysaccharides on the outer leaflet of the asymmetric outer membrane bilayer of these bacteria prevent drug entry. Furthermore, since hospitalised and critically ill patients are increasingly experiencing antibiotic-resistant bacterial infections, the emergence of antibiotic resistance in bacteria—especially Gram-negative bacteria like Acinetobacter baumannii—is a rapidly growing global health concern.
The bacterial cell’s inner membrane is where lipopolysaccharide synthesis takes place. It is then transferred across the cell membrane and assembled in the outer leaflet. Lipopolysaccharides are transported by means of LptB2FGC, an inner membrane subcomplex that uses a protein bridge and the hydrolysis of adenosine triphosphate (ATP) to extract lipopolysaccharides from the inner membrane and transfer them to the outer membrane. By specifically targeting this transportation complex, antibacterial activity may be able to successfully disrupt the lipopolysaccharide production, rendering Gram-negative bacteria vulnerable.
Regarding the research
The two investigations explained how bacterial lipopolysaccharide was prevented from being transported from the inner membrane and, as a result, from assembling on the outer membrane by using macrocyclic peptides that target the LptB2FGC transportation machinery in A. baumannii and A. baylyi. Tethered macrocyclic peptides are a novel family of antibiotics that Zampaloni et al. found and optimised. These antibiotics prevent lipopolysaccharide from being transported across the bacterial membrane. They also used in vitro and in vivo testing on animal models to choose Zosurabalpin, an antibiotic candidate, for clinical testing.
Nearly 45,000 macrocyclic peptides were tested in the study against different strains of human-infecting Gram-positive and Gram-negative pathogens using whole-cell phenotyping screening. Furthermore, the potential therapeutic efficacy of certain macrocyclic peptides against infections caused by Carbapenem- and multidrug-resistant strains of A. baumannii was evaluated in animal models. Furthermore, zwitterionic tethered macrocyclic peptides were investigated to increase the treatment’s potency and tolerance based on the tolerability findings from the in vivo trials in the mice models.
In order to comprehend the chemical mechanisms by which zosurabalpin prevents lipopolysaccharide from being extracted across the membrane bilayer, Pahil et al. conducted a second investigation. To do this, they employed cryo-electron microscopy to ascertain the binding configuration of three macrocyclic peptides, including zosurabalpin, with the A. baylyi LptB2FGC transporter. In order to determine whether structural changes to the lipopolysaccharide might affect how well Zosurabalpin inhibits lipopolysaccharide transport, the study also employed point mutants.
To further understand how well the three macrocyclic peptides (Zosurabalpin, RO7196472, and RO7075573) bound to the lipopolysaccharide-LptB2FGC complex, cryo-electron microscope structures of the complex containing LptB2FGC transporter and lipopolysaccharide were employed. Additionally, they made an effort to determine how the three macrocyclic peptides’ various structural variations affected the binding efficiency of each one.
Outcomes
The Zampaloni et al. study’s findings demonstrated that the new class of antibiotics made up of macrocyclic peptides could treat infections brought on by Carbapenem-resistant A. baumannii in both in vitro and in vivo environments, demonstrating the ability to get past the bacteria’s developed drug-resistance mechanisms. The medication was also effective against Acinetobacter strains that were resistant to many drugs. The development of the clinically tested medication Zosurabalpin was made possible in part by the optimisation of the physico-chemical characteristics of macrocyclic peptides through the use of a serum precipitation experiment.
In the in vivo investigations using mouse models of infection, zosurabalpin showed favourable safety and pharmacokinetic characteristics, including effectiveness against sepsis and lung and thing infections brought on by Carbapenem-resistant A. baumannii strains. According to the experts, human clinical trials are being conducted to develop Zosurabalpin for human use because they think the medication is safe and effective enough to test on humans.
The study conducted by Pahil et al. provided additional insight into the molecular mechanism by which macrocyclic peptides, including Zosurabalpin, effectively impede the transit of lipopolysaccharide into the outer membrane. These macrocyclic peptides recognise and bind to a composite binding site made up of the lipopolysaccharide and the LptB2FGC transporter, which is how they trap the lipopolysaccharide-LptB2FGC transporter complex, according to a combination of genetic, biochemical, and structural investigations.
In conclusion
Overall, the results of these investigations demonstrated that infections brought on by Carbapenem- and multidrug-resistant A. baumannii strains can be successfully treated by a novel class of antibiotics made up of macrocyclic peptides, as demonstrated by both in vitro and in vivo trials.
Moreover, the outcomes have established the framework for human clinical studies aimed at evaluating the safety and effectiveness of the macrocyclic peptide Zosurabalpin in treating drug-resistant Acinetobacter infections in people. By enclosing the lipopolysaccharide-LptB2FGC transporter complex and inhibiting its ability to export lipopolysaccharide to the outside membrane, these drugs cure the infection.
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