Vancomycin was originally isolated by Dr. Kornfield in 1952 from a microbial fermentation product collected in the soil of Borneo. At that time, the compound only had a simple number, 05865, and it was brown due to the presence of other trace impurities, so it was also called Mississippi mud (Mississippi mud). However, many experiments have proved that 05865 has a good inhibitory effect on penicillin-resistant strains. After further purification by ion exchange resin, the compound entered clinical trials and was named vancomycin. In 1996, Sheldrick published the crystal structure of vancomycin, confirming its existence in dimer form. It was the first glycopeptide antibiotic to prevent or treat infections caused by Gram-positive bacteria and was once used as a "last line of defense" against infections because it treated infections for which all other antibiotics were ineffective. However, with the increase of use time, vancomycin also faces the crisis of drug resistance.

Resistance Mechanisms and Structural Modifications Most Gram-negative bacteria are naturally resistant to vancomycin due to their outer membranes that prevent the penetration of macromolecules. Other gram-positive bacteria are also inherently resistant, but these bacteria rarely infect humans. Although natural resistance limits the use of antibiotics, another problem that has plagued humans for a long time is the acquired resistance caused by the long-term use of antibiotics. Vancomycin specifically binds to the D-alanyl-D-alanine structure, but the cell wall of drug-resistant pathogens is formed by D-alanyl-D-lactic acid, and a corresponding ligase catalyzes the glycopeptide chain cross-linking between cells, thereby evading the inhibitory effect of vancomycin on cell wall synthesis. Vancomycin is the "last line of defense" against Gram-positive bacteria, and the emergence of its drug-resistant pathogens makes humans face difficulties.

In 2009, Jorgensen et al. found by calculation that the activity of vancomycin derivatives was greatly improved when the 3-hydroxyl group of the 7-position residue was substituted by a smaller alkyl or alkoxy group. Soon they found that substitution of the peptide bond between residues 4 and 5 could also improve the activity of the derivatives. Although these modifications can improve the activity of vancomycin, they still cannot kill the resistant bacteria, and can only rely on other new antibiotics such as daptomycin for anti-infective treatment.

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