| The discovery of antibacterial drugs is a landmark in the history of drug discovery.But nowadays,the abuse of antibacterial drugs has accelerated the evolution of bacteria.However,due to the longer development process of antibacterial drugs and lower profits than other drugs(anticancer drugs etc.),the development of new antibacterial drugs was always stagnant.The resistance of bacteria to existing drugs and the lack of new drugs have contributed to the multidrug resistance and even super bacteria.In order to promote the development and application of antibacterial drugs,the research was carried out based on the two key proteins of bacteria,DprE1 and MscL.On the one hand,tuberculosis,as the number one killer of death caused by infection,is responsible for a great threat to human life and health.Despite the increasing need of new antituberculosis drugs,the number of agents approved for the market has fallen to an all-time low.In response to the emerging drug resistance followed,structurally unique chemical entities will be highlighted.Decaprenylphosphoryl-?-D-ribose oxidase(DprE1)participating in the biosynthesis of mycobacterium cell wall is a highly vulnerable and validated antituberculosis target.On the basis of it,a systematic strategy was applied to identify a high-quality lead compound(compound 50)that inhibits the essential enzyme DprE1,thus blocking the synthesis of the mycobacterial cell wall to kill M.tuberculosis in vitro and in vivo.Correspondingly,the rational design and synthetic strategy for compound 50 was reported.Notably,the compound 50 has been confirmed to be no toxicity.Altogether,our data suggest the compound 50 targeting DprE1 is a promising candidate or lead compound for the tuberculosis therapy.And our research can provide a model for drug development of other diseases.On the other hand,MscL is present in most bacteria.As an emergency release valve and a final setting,MscL is capable of releasing the solute when the external osmotic pressure suddenly changes,ensuring the survival of bacteria in extreme environments.And no analogs were found in eukaryotes.Due to the unique and conserve structure,MscL may become a potent drug target for combating bacteria and even super bacteria.In this paper,combined with gene knockout technique,recombinant DNA technology,membrane protein purification technology,MST and molecular docking et al.,we identified that three antibiotics(dihydrostreptomin,spectomicn and nituroxside)directly bind to MscL and pass into bacteria.It must also be noted that MscL is not the only channel for the three antibiotics to enter bacteria.In addition,we predict that the two other important mechanical channels,Msc S and Msc K,may act as the efflux channels for antibiotic,which have antagonistic effects on antibiotics.In summary,our research illustrates the important role of MscL in the antibacterial mechanism of antibiotics and highlights potential advantages of the channel in the development of antibacterial drugs.In addition,a research strategy to explore the action mode of unknown target via known drugs is reported.Furthermore,it can also be applied to the study of other targets and mechanisms of disease.Herein,our research uses virtual screening method combined with activity verification to discover a safe and effective anti-tuberculosis candidate,quickly and accurately.Otherwise,our data strongly suggest that three antibiotics mostly depend on MscL to enter the bacteria,emphasizing the importance of MscL for the antimicrobial study.These results may provide guiding significance and reference for the research of antibacterial drugs. |
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