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New antibiotics attack resistance
Chemically optimized, natural products such as Arylomycin can be compounds that have potent, broad-spectrum antibacterial activity against multi-drug resistant Gram-negative bacteria such as E. coli. The latest research in this in vitro and mouse experiment, published recently in Nature, is expected to make these compounds a new and essential drug to counter a serious threat to global health.
Multi-drug resistant bacteria are increasing, and ESKAPE pathogens cause intractable multi-drug resistant infections, so the risk is also the most serious; in ESKAPE, Gram-negative bacteria (such as Escherichia coli, Klebsiella pneumoniae, and patina) Pseudomonas and Acinetobacter baumannii are particularly threatened – their double-layered outer membrane prevents many antibiotics from reaching the target. Despite a lot of efforts by researchers, over the past 50 years, there have been no new antibiotics with antibacterial activity against Gram-negative bacteria.
Arylomycin is a class of macrocyclic lipopeptides that inhibit type I signal peptidase (SPase), a key membrane-bound enzyme that breaks down proteins and peptides. In Gram-negative bacteria, the active site of SPase is located between the bacterial cell membrane and the bacterial outer membrane. Researchers have thought that Arylomycin could not reach this active site because Arylomycin could not penetrate the bacterial outer membrane.
Christopher Heise and colleagues at Genentech, Calif., found a synthetic Arylomycin derivative called G0775 in the process of finding Arylomycin derivatives with better affinity and stronger outer membrane penetration. ESKAPE pathogens have potent in vitro antibacterial activity and can penetrate the bacterial outer membrane through an atypical mechanism.
The researchers found that super multidrug-resistant strains resistant to almost all known antibiotics are still sensitive to G0775 and have a lower incidence of drug resistance. The antibacterial efficacy of G0775 against Gram-negative pathogens was confirmed in multiple infected mouse models.
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