J. Med. Chem.: a new antibiotic developed by Shanghai Institute of medicine can inhibit vancomycin resistant bacteria

Antibiotic resistance of bacteria has become an increasingly serious global public health problem, and all kinds of drug-resistant "super bacteria" threaten human health and life In recent years, the World Health Organization has issued many reports, pointing out that at present, the research and development of new antibiotics is seriously insufficient, and it is difficult to face the increasingly serious threat of drug-resistant bacteria infection Many countries and institutions began to take incentive measures to encourage the development of new anti (drug-resistant) bacteria drugs Vancomycin, a glycopeptide antibiotic, has been known as the "ultimate antibiotic" for human beings to deal with the superbacterium MRSA (methicillin resistant S.aureus) However, after 2002, vancomycin resistant S.aureus (visa) and vancomycin resistant S.aureus (VRSA) strains appeared In addition, the threat of vancomycin resistant enterococci (VRE) to human is increasing all over the world According to the data analysis of domestic infection cases, more than 10 million people are infected with MRSA, VRSA, VRE and other drug-resistant bacteria every year, so it is urgent to develop new drug-resistant bacteria The structure of vancomycin and its analogues, the extra sugar part or hydrophilic group is shown as red (source: J Med Chem.) Recently, Huang Wei Group and lanloff group of Shanghai Institute of medicine, Chinese Academy of Sciences published papers on Journal of medical chemistry, reporting the new glycopeptide antibiotic derivatives The antibacterial activity of Staphylococcus aureus and Enterococcus faecalis was 128-1024 times higher than that of vancomycin Synthesis of novel vancomycin derivatives (source: J Med Chem.) In view of the mechanism of vancomycin resistance, the research team increased the membrane permeability of drug-resistant bacteria by introducing hydrophobic groups on the basis of vancomycin structure, and introduced sugar structure fragments to promote the combination of drugs and peptide glycan precursor ligands of bacterial cell wall, which significantly enhanced the effect of drug-resistant bacteria Mic decreased by 2-3 orders of magnitude In the aspect of drug formation, reasonable structural modification has good advantages in the aspects of pharmacokinetics and safety evaluation in vivo The hydrophobic group prolongs the half-life of the drug, improves AUC, and the hydrophilic sugar structure regulates the in vivo clearance rate and avoids accumulated toxicity The half-life of sm-v-61 is 5 times of vancomycin and AUC is 15 times of vancomycin In terms of safety, sm-v-61 has less hepatorenal cytotoxicity than vancomycin The acute toxicity test in rats showed that there was no obvious adverse reaction at 40 times of the effective dose At present, the project is undergoing systematic preclinical evaluation to prepare for clinical application Paper link: http://pubs.acs.org/doi/10.1021/acs.jmedchem.7b01345 correspondence Author: Huang Wei http://sourcedb.simm.cas.cn/zw/zjrc/201308/t2013809_.html lanlefu http://sourcedb.simm.cas.cn/zw/zjrc/201009/t2010099_.html