Nat Microbiol. The Zhu Kui/Shen Jianzhong team discovered a new broad-spectrum antibacterial additive.

Since the discovery of penicillin, a large number of natural and synthetic antibacterial drugs have been developed and used, which has become a powerful weapon against bacterial infection. However, due to the large-scale and irrational use of antibiotics, the generation and spread of drug-resistant bacteria are accelerated, resulting in the reduction of the efficacy of a variety of antimicrobial agents against bacterial infection, or even ineffective.in order to ensure the sustainable development of human health and animal husbandry, it is imperative to develop effective treatment programs and find new antimicrobial agents or antibacterial synergists.the research and development cost of new antibacterial drugs and substitutes is high, and the cycle is long; compared with the development of new drugs, improving the efficacy of existing antibacterial drugs is relatively low cost, safe and efficient, which has become a research hotspot in recent years.at present, there are two kinds of antibacterial synergists commonly used in clinic, which are sulfanilamide synergist and β - lactamase inhibitor, which were listed in the 1970s and 1980s respectively.these two kinds of synergists can only enhance the therapeutic effect of a certain class of antibiotics. However, with the widespread prevalence of multi drug resistant bacteria, especially gram-negative drug-resistant bacteria, the single mechanism of their action has led to the lack of clinical application of these two kinds of synergists.on May 18, 2020, Professor Zhu Kui and academician Shen Jianzhong of China Agricultural University published a research paper entitled "a broad-spectrum antibacterial advance reverses multidrug resistant gram negative pathways" online on nature microbiology.in this study, a novel linear peptide, slap-s25, was found to have antibacterial effect on a variety of Gram-negative bacteria. At the same time, slap-s25 can be used as an Antibiotic synergist to improve the antibacterial effect of several antibiotics including tetracycline, vancomycin, ofloxacin, rifampicin and polymyxin against multidrug-resistant Escherichia coli.in this study, a novel linear short chain broad-spectrum antibacterial synergist slap-s25 was reported for the first time, which can improve the antibacterial effect of several commonly used clinical antibiotics such as tetracycline, vancomycin, ofloxacin, rifampicin and polymyxin against multidrug-resistant Escherichia coli and other gram-negative bacteria.studies have shown that the combination of slap-s25 and polymyxin can restore the sensitivity of 10 different polymyxin resistant gram-negative bacteria to polymyxin, but for Klebsiella pneumoniae, the combination strategy of slap-s25 and other antibiotics should be adopted. At the same time, the combination of slap-s25 and polymyxin effectively inhibited the growth of 87 clinical isolates of polymyxin resistant Escherichia coli. In addition, slap-s25 can not only restore the sensitivity of Gram-negative bacteria carrying polymyxin resistant gene MCR to polymyxin, but also reduce the dosage of polymyxin. It provides a new way of thinking and technical support for the protection of polymyxin drugs as the "last line of defense" against Gram-negative bacteria infection. The structure-activity relationship analysis revealed that the benzene side chain of slap-s25 was the active center.it was found that the binding of slap-s25 with lipopolysaccharide (LPS), the main component of outer membrane of Gram-negative bacteria, destroyed the integrity of outer membrane and increased the permeability of outer membrane.interestingly, the binding of slap-s25 to LPS was not affected by MCR enzyme modification.subsequently, slap-s25 targeted to recognize phosphatidylglycerol (PG) in the bacterial intima, and speculated that it combined with the phosphate radical of the PG head group to increase the permeability of bacterial intima.slap-s25 can greatly improve the permeability of the inner and outer membrane of Gram-negative bacteria through dual effects, and promote the accumulation of a variety of antibacterial drugs in the bacteria, so as to play a synergistic effect.it is worth noting that PG is a ubiquitous membrane phospholipid molecule in bacterial endomembrane, but its content is very low in mammals.this further explains the high selectivity and safety of slap-s25, which ensures low cytotoxicity and hemolysis, and has good potential as a patent drug.in animal infection models, including larva borer bacterial infection model, mouse peritonitis septicemia model and mouse leg infection model, the combined application of slap-s25 and polymyxin significantly increased the survival rate of multi drug resistant E.coli infection, and reduced the bacterial load in heart, liver, spleen, lung, kidney and other organs of mice.in addition, the combination of slap-s25 and polymyxin also significantly reduced the bacterial load in the leg of mice. the above results showed that slap-s25 is a new kind of lead compound of antibacterial synergist, and has ideal drug-forming properties. at the same time, the newly discovered drug target PG provides a new idea for the screening of active molecules and the development of new antibacterial drugs. in the future, we will carry out in-depth research on the mechanism of slap-s25 to lay a foundation for its clinical application, and realize the efficient treatment of multidrug-resistant gram-negative pathogens infection. original link: